4-methylpyridopyrimidinone compounds

ABSTRACT

The present invention is directed to novel 4-methylpyridopyrimidinone compounds of Formula (I), 
                         
and to salts thereof, their synthesis, and their use as inhibitors of phosphoinositide 3-kinase alpha (PI3-Kα).

This application is a continuation of U.S. patent application Ser. No.11/854,999, filed Sep. 13, 2007, now U.S. Pat. No. 7,696,213, whichclaims the benefit of U.S. Provisional Application No. 60/845,065 filedSep. 15, 2006, U.S. Provisional Application No. 60/947,852 filed Jul. 3,2007, and U.S. Provisional Application No. 60/952,628 filed Jul. 30,2007, the contents of which are hereby incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The present invention is directed to novel 4-methylpyridopyrimidinonecompounds, and salts thereof, their synthesis, and their use asmodulators or inhibitors of the phosphoinositide 3-kinase alpha (PI3-Kα)enzyme. The compounds of the present invention are useful for modulating(e.g. inhibiting) PI3-Kα activity and for treating diseases orconditions mediated by PI3-Kα, such as for example, disease statesassociated with abnormal cell growth such as cancer.

BACKGROUND

Phosphoinositide 3-kinases (PI3-Ks) catalyze the synthesis of thephosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P₂, andPI(3,4,5)P₃ (PIP₃). (Fruman et al., Phosphoinositide kinases, Annu. Rev.Biochem. 67 (1998), pp. 481˜507; Knight et al., A Pharmacological Map ofthe PI3-K Family Defines a Role for p110α in Insulin Signaling, Cell 125(2006), pp. 733-747.) In the appropriate cellular context, these threelipids control diverse physiological processes including cell growth,survival, differentiation, and chemotaxis. (Katso et al., Cellularfunction of phosphoinositide 3-kinases: implications for development,homeostasis, and cancer, Annu. Rev. Cell Dev. Biol. 17 (2001), pp.615-675.) The PI3-K family comprises at least 15 different enzymes,sub-classified by structural homology, with distinct substratespecificities, expression patterns, and modes of regulation. The mainPI3-kinase isoform in cancer is the Class I PI3-Kα, consisting ofcatalytic (p110α) and adapter (p85) subunits. (Stirdivant et al.,Cloning and mutagenesis of the p110α subunit of human phosphoinositide3′-hydroxykinase, Bioorg. Med. Chem. 5 (1997), pp. 65-74.)

The 3-phosphorylated phospholipids (PIP₃s) generated by PI3-Ks act assecond messengers recruiting kinases with lipid binding domains(including plekstrin homology (PH) regions), such as Akt andphosphoinositide-dependent kinase-1 (PDK1). (Vivanco & Sawyers, ThePhosphatidylinositol 3-Kinase-Akt Pathway In Human Cancer, NatureReviews Cancer 2 (2002), pp. 489-501.) Binding of Akt to membrane PIP₃scauses the translocation of Akt to the plasma membrane, bringing Aktinto contact with PDK1, which is responsible for activating Akt. Thetumour-suppressor phosphatase, PTEN, dephosphorylates PIP₃ and thereforeacts as a negative regulator of Akt activation. The PI3-Ks, Akt and PDK1are important in the regulation of many cellular processes includingcell cycle regulation, proliferation, survival, apoptosis and motilityand are significant components of the molecular mechanisms of diseasessuch as cancer, diabetes and immune inflammation. Several components ofthe PI3-K/Akt/PTEN pathway are implicated in oncogenesis. In addition togrowth factor receptor tyrosine kinases, integrin-dependent celladhesion and G-protein coupled receptors activate PI3-K both directlyand indirectly through adaptor molecules. Functional loss of PTEN (themost commonly mutated tumour-suppressor gene in cancer after p53),oncogenic mutations in the PIK3CA gene encoding PI3-Kα, amplification ofthe PIK3CA gene and overexpression of Akt have been established in manymalignancies. (see, for example, Samuels, et al., High frequency ofmutations of the PIK3CA gene in human cancers, Science 304 (2004), p.554; Broderick et al., Mutations in PIK3CA in anaplasticoligodendrogliomas, high-grade astrocytomas, and medulloblastomas,Cancer Research 64 (2004), pp. 5048-5050.)

PI3-Kα is thus an attractive target for cancer drug development sincesuch agents would be expected to inhibit proliferation and surmountresistance to cytotoxic agents in cancer cells. There is a need toprovide new PI3-Kα inhibitors that are good drug candidates. They shouldbe bioavailable, be metabolically stable and possess favorablepharmacokinetic properties.

SUMMARY

In one embodiment of the present invention is a compound of Formula (I)

or a salt thereof,wherein:

R¹ is H or (C₁ to C₆) alkyl optionally substituted with at least one R⁵group;

A is a 3 to 10 membered cycloalkyl group;

R² is (C₁ to C₆) alkyl substituted with at least one R⁶ group, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ toC₉) heteroaryl, —NR^(7a)R^(7b), or —N═CR^(8a)R^(8b) wherein each of thesaid (C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄)aryl, and (C₂ to C₉) heteroaryl is optionally substituted with at leastone R⁹ group;

R³ is (C₁ to C₆) alkyl, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, (C₂ to C₈) alkenyl, (C₂ to C₈) alkynyl, halogen,cyano, —(CH₂)_(n)C(O)OR¹⁰, —(CH₂)_(n)C(O)N(R^(11a)R^(11b)), COR¹², (C₆to C₁₄) aryl, or (C₂ to C₉) heteroaryl, wherein said (C₁ to C₆) alkyl,(C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₈) alkenyl,(C₂ to C₈) alkynyl, (C₆ to C₁₄) aryl and (C₂ to C₉) heteroaryl isoptionally substituted with at least one R⁹ group;

each R⁴ is independently —OH, halogen, CF₃, —NR^(11a)R^(11b)(C₁ to C₆)alkyl, (C₁ to C₆) alkenyl, (C₁ to C₆) alkynyl, (C₁ to C₆) alkoxy, cyano,(C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl,(C₂ to C₉) heteroaryl, —C(O)R¹²—C(O)NR^(11a)R^(11b), —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —NR^(11a)S(O)_(m)R¹²—(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₁ to C₆)alkyl, (C₁ to C₆) alkenyl, (C₁ to C₆) alkynyl, (C₁ to C₆) alkoxy, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₂) aryl, and (C₂to C₉) heteroaryl is optionally substituted with at least one R¹³ group;

each R⁵ is independently —OH, halogen, CF₃, —NR^(11a)R^(11b), (C₁ to C₆)alkyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉) heteroaryl, —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —C(O)R¹² or —C(O)NR^(11a)R^(11b) wherein eachof the said (C₁ to C₆) alkyl, (C₁ to C₆) alkoxy, (C₃ to C₁₀) cycloalkyl,(C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, and (C₂ to C₉) heteroarylis optionally substituted with at least one R⁹ group;

each R⁶ is independently —OH, (C₁ to C₆) alkynyl, cyano, (C₃ to C₁₀)cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉)heteroaryl, —C(O)R¹²—C(O)NR^(11a)R^(11b), —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —NR^(11a)S(O)_(m)R¹²—(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₁ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ toC₁₂) aryl, and (C₂ to C₉) heteroaryl is optionally substituted with atleast one R¹³ group;

R^(7a) and R^(7b) are each independently H, (C₁ to C₆) alkyl, (C₂ toC₆)alkenyl, (C₂ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl, or (C₆ toC₁₀)aryl, wherein each of the said (C₁ to C₆) alkyl, (C₂ to C₆)alkenyl,(C₂ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl, and (C₆ to C₁₀)aryl isoptionally substituted with at least one R⁹ group; or R^(7a) and R^(7b)may be taken together with the nitrogen atom to form a 5 to 8 memberedheterocyclyl ring, wherein said heterocyclyl ring has 1 to 3 ringheteroatoms selected from the group consisting of N, O, and S andwherein the said 5 to 8 membered cycloheteroalkyl ring is optionallysubstituted with at least one R⁹ group;

R^(8a) and R^(8b) are each independently H, (C₁ to C₆) alkyl, or (C₃ toC₁₀) cycloalkyl wherein each of the said (C₁ to C₆) alkyl, and (C₃ toC₁₀) cycloalkyl, is optionally substituted with at least one R⁹ group;

each R⁹ is independently —OH, halogen, CF₃, —NR^(11a)R^(11b), (C₁ to C₆)alkyl, (C₁ to C₆) alkenyl, (C₁ to C₆) alkynyl, (C₁ to C₆) alkoxy, cyano,(C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl,(C₂ to C₉) heteroaryl, —C(O)R¹²—C(O)NR^(11a)R^(11b), —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —NR^(11a)S(O)_(m)R¹²—(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₁ to C₆)alkyl, (C₁ to C₆) alkenyl, (C₁ to C₆) alkynyl, (C₁ to C₆) alkoxy, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₂) aryl, and (C₂to C₉) heteroaryl is optionally substituted with at least one R¹³ group;

each R¹⁰ is independently H, or (C₁ to C₆) alkyl;

R^(11a) and R^(11b) are each independently H, (C₁ to C₆) alkyl, (C₂ toC₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, or (C₆ to C₁₂) aryl whereineach of the said (C₁ to C₆) alkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ toC₉) heteroaryl, and (C₆ to C₁₂) aryl is optionally substituted with atleast one R¹³ group;

each of the R¹² is independently (C₁ to C₆) alkyl, (C₃ to C₁₀)cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, or (C₆to C₁₄) aryl wherein each of the said (C₁ to C₆) alkyl, (C₃ to C₁₀)cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, and (C₆to C₁₄) aryl is optionally substituted with at least one R¹³ group;

each of the R¹³ is independently —OH, halogen, CF₃, (C₁ to C₆) alkyl,(C₁ to C₆) alkenyl, (C₁ to C₆) alkynyl, (C₁ to C₆) alkoxy, cyano, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ toC₉) heteroaryl, amino, carbonyl, C-amido, sulfinyl, S-sulfonamido,C-carboxyl, N-amido, or N-carbamyl;

each m is independently 1 or 2;

each n is independently 0, 1, 2, 3, or 4; and

each z is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7,or 8.

One aspect of this embodiment is a compound according to Formula (I), asdescribed above, wherein A is selected from the group consisting ofcyclobutyl, cyclopentyl, and cyclohexyl.

A further aspect of this embodiment is a compound according to Formula(I), as described above, wherein R³ is (C₆ to C₁₄) aryl or (C₂ to C₉)heteroaryl, wherein said (C₆ to C₁₄) aryl or (C₂ to C₉) heteroaryl isoptionally substituted with at least one R⁹ group.

A further aspect of this embodiment is a compound according to Formula(I), as described above, which is selected from the group consisting of:2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-quinolin-3-ylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-bromo-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-{[(2S)-2,3-dihydroxypropyl]oxy}cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-quinolin-3-ylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-bromo-8-[cis-4-(2-hydroxyethoxy)cyclohexyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-[6-(dimethylamino)pyridin-3-yl]-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-({trans-4-[2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide;methyl({trans-4-[2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetate;2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one,2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one,2-({cis-4-[2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({cis-4-[2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({cis-4-[2-amino-4-methyl-7-oxo-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({cis-4-[2-amino-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({cis-4-[2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-{[cis-4-(2-amino-4-methyl-7-oxo-6-quinolin-3-ylpyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl]oxy}acetamide,2-({trans-4-[2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-{[trans-4-(2-amino-4-methyl-7-oxo-6-quinolin-3-ylpyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl]oxy}acetamide,2-({trans-4-[2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({trans-4-[2-amino-4-methyl-7-oxo-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-({trans-4-[2-amino-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetamide,2-amino-8-[trans-3-(2-hydroxyethoxy)cyclobutyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-8-[trans-3-(2-hydroxyethoxy)cyclobutyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,2-amino-8-[trans-3-(2-hydroxyethoxy)cyclobutyl]-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,2-({trans-3-[2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclobutyl}oxy)acetamide,2-({trans-3-[2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclobutyl}oxy)acetamide,2-({trans-3-[2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclobutyl}oxy)acetamide,or the salt thereof.

A further aspect of the present invention is a compound of Formula (II)

or a salt thereof,wherein:

R¹ is H or (C₁ to C₆) alkyl optionally substituted with at least one R⁴group;

R² is (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, (C₃ to C₁₀) cycloalkyl, (C₅to C₈) cycloalkenyl, (C₂ to C₉) cycloheteroalkyl, or —(CH₂)_(n)(C₆ toC₁₄) aryl, wherein said (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, (C₃ toC₁₀) cycloalkyl, (C₅ to C₈) cycloalkenyl, (C₂ to C₉) cycloheteroalkyl,and —(CH₂)_(n)(C₆ to C₁₄) aryl is optionally substituted with at leastone R⁴ group;

R³ is (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, cyano, —(CH₂)_(n)C(O)OR^(5a)or —(CH₂)_(n)C(O)N(R^(5a)R^(5b)), wherein said (C₁ to C₆) alkyl or (C₂to C₈) alkenyl is optionally substituted with at least one R⁴ group;

each R⁴ is independently —OH, halogen, CF₃, —NR^(5a)R^(5b), (C₁ to C₆)alkyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₁₀) cycloalkyl,—S(O)_(m)R^(5a), —S(O)_(m)NR^(5a)R^(5b), —C(O)R^(5a) or—C(O)NR^(5a)R^(5b);

R^(5a) and R^(5b) are each independently H, (C₁ to C₆) alkyl, (C₂ to C₉)cycloheteroalkyl, (C₂ to C₉) heteroaryl, or (C₆ to C₁₄) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4.

A further aspect of this embodiment is a compound of Formula (II),wherein R³ is —(CH₂)_(n)C(O)N(R^(5a)R^(5b)).

A further aspect of this embodiment is a compound of Formula (II),wherein R² is selected from the group consisting of isopropyl, allyl,cyclopentyl, cyclobutyl, hydroxycyclohexyl, hydroxycyclopentyl,hydroxycyclobutyl, hydroxycycloheptyl, methoxyethyl, methoxypropyl,ethyl, methyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxylbutyl, methoxybenzyl, andchlorobenzyl.

A further aspect of the present invention is a compound according toFormula (II), as described above, which is selected from the groupconsisting of:2-Amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-N-1H-pyrazol-5-yl-78-dihydropyrido[23-d]pyrimidine-6-carboxamide;2-amino-N-(1-ethyl-1H-pyrazol-5-yl)-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[23-d]pyrimidine-6-carboxamide;8-Cyclopentyl-4-methyl-2-methylamino-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid (1H-pyrazol-3-yl)-amide;2-amino-8-isopropyl-4-methyl-7-oxo-N-1H-pyrazol-5-yl-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;2-amino-N-(1-ethyl-1H-pyrazol-5-yl)-8-isopropyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;8-cyclopentyl-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;8-cyclopentyl-4-methyl-2-(methylamino)-7-oxo-N-pyridin-2-yl-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;and8-cyclopentyl-N-isoxazol-3-yl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide,or the salt thereof.

A further aspect of the present invention is a compound of Formula (III)

or a salt thereof,wherein:

R¹ is H or (C₁ to C₆) alkyl optionally substituted with at least one R⁴group;

R² is a spirocyclyl group optionally substituted with at least one R⁴group;

R³ is (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, cyano, —(CH₂)_(n)C(O)OR⁵,—(CH₂)_(n)C(O)N(R^(6a)R^(6b)), (C₆ to C₁₄) aryl, or (C₂ to C₉)heteroaryl, wherein said (C₁ to C₆) alkyl or (C₂ to C₈) alkenyl isoptionally substituted with at least one R⁴ group, and wherein said (C₆to C₁₄) aryl or (C₂ to C₉) heteroaryl is optionally substituted with atleast one R⁷ group;

each R⁴ is independently —OH, halogen, CF₃, —NR^(6a)R^(6b), (C₁ to C₆)alkyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₈) cycloalkyl, —S(O)_(m)R^(6a),—S(O)_(m)NR^(6a)R^(6b), —C(O)R^(6a) or —C(O)NR^(6a)R^(6b);

each R⁵ is independently H, or (C₁ to C₆) alkyl;

R^(6a) and R^(6b) are each independently H, (C₁ to C₆) alkyl, (C₂ to C₉)cycloheteroalkyl, (C₂ to C₉) heteroaryl, or (C₆ to C₁₄) aryl;

each of R⁷ is independently —OH, halogen, —NR^(6a)R^(6b), cyano, (C₁ toC₆) alkyl, (C₁ to C₆) alkoxy, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, —S(O)_(m)R^(6a), —S(O)_(m)NR^(6a)R^(6b),—(CH₂)_(n)C(O)OR⁵, —(CH₂)_(n)C(O)N(R^(6a)R^(6b)), —OC(O)R^(6a), or—NR^(6a)C(O)R^(6b) wherein each of said (C₁ to C₆) alkyl, (C₁ to C₆)alkoxy, (C₂ to C₉) cycloheteroalkyl, and (C₃ to C₁₀) cycloalkyl isoptionally substituted with at least one R⁴ group;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4.

A further aspect of the present invention is a compound selected fromthe group consisting of:2-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(cis-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-[6-(dimethylamino)pyridin-3-yl]-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-6-quinolin-3-ylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-6-(6-pyrrolidin-1-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-8-(cis-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(6-ethoxypyridin-3-yl)-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-[6-(dimethylamino)pyridin-3-yl]-8-(cis-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-methoxycyclohexyl)-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(cis-4-hydroxy-4-methylcyclohexyl)-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(cis-4-hydroxycyclohexyl)-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-6-(5-fluoro-6-methoxypyridin-3-yl)-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-8-(trans-4-hydroxycyclohexyl)-6-(2-methoxypyrimidin-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-[(2,2-difluoroethyl)amino]-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,or the salt thereof.

In a further embodiment is any of the aspects described above incombination with any of the other aspects described above which is notinconsistent therewith.

The present invention also relates to a pharmaceutical composition,comprising at least one compound as described herein, or a salt thereof,and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to a method of treating abnormal cellgrowth, or any PI3-Kα-mediated disease or condition, in a mammal in needthereof, comprising the step of administering to said mammal atherapeutically effective amount of at least one compound as describedherein, or a salt thereof. For example, in one embodiment the abnormalcell growth is cancerous. In a further embodiment, the abnormal cellgrowth is non-cancerous.

The present invention further relates to a method of inhibiting PI3-Kαenzymatic activity, comprising contacting a PI3-Kα enzyme with aPI3-Kα-inhibiting amount of at least one compound as described herein,or a salt thereof.

The present invention further relates to the use of any of the compoundsas described herein, or a salt thereof, in the manufacture of amedicament for the treatment of abnormal cell growth in a mammal.

The present invention further relates to methods of making the compoundsas described herein using the methods as shown in the specific examplesherein and in the general synthetic methods A, B, C, D, E, F, H and I asdescribed herein.

The present invention further relates to any of the compounds describedabove, or salts thereof, for use as a medicament. The present inventionfurther relates to the use of any of the compounds described above, orsalts thereof, for the manufacture of a medicament for the treatment ofabnormal cell growth.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of dose-dependent anti-tumor efficacy of2-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 152) in the PC3 tumor model.

FIG. 2 shows an example of dose-dependent anti-tumor efficacy ofCompound 152 in the SKOV3 tumor model.

FIG. 3 shows an example of dose-dependent anti-tumor efficacy ofCompound 152 in the U87MG tumor model.

DETAILED DESCRIPTION

As used herein, the terms “comprising” and “including” are used in theiropen, non-limiting sense.

The terms “halo” and/or “halogen” refer to fluorine, chlorine, bromineor iodine.

The term “(C₁ to C₆)” alkyl refers to a saturated aliphatic hydrocarbonradical including straight chain and branched chain groups of 1 to 6carbon atoms. Examples of (C₁ to C₆) alkyl groups include methyl, ethyl,propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.The terms “Me” and “methyl,” as used herein, mean a —CH₃ group. Theterms “Et” and “ethyl,” as used herein, mean a —C₂H₅ group.

The term “(C₂ to C₈) alkenyl”, as used herein, means an alkyl moietycomprising 2 to 8 carbons having at least one carbon-carbon double bond.The carbon-carbon double bond in such a group may be anywhere along the2 to 8 carbon chain that will result in a stable compound. Such groupsinclude both the E and Z isomers of said alkenyl moiety. Examples ofsuch groups include, but are not limited to, ethenyl, propenyl, butenyl,allyl, and pentenyl. The term “allyl,” as used herein, means a—CH₂CH═CH₂ group. The term, “C(R)═C(R),” as used herein, represents acarbon-carbon double bond in which each carbon is substituted by an Rgroup.

As used herein, the term “(C₂ to C₈) alkynyl” means an alkyl moietycomprising from 2 to 8 carbon atoms and having at least onecarbon-carbon triple bond. The carbon-carbon triple bond in such a groupmay be anywhere along the 2 to 8 carbon chain that will result in astable compound. Examples of such groups include, but are not limitedto, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne,2-hexyne, and 3-hexyne.

The term “(C₁ to C₈) alkoxy”, as used herein, means an O-alkyl groupwherein said alkyl group contains from 1 to 8 carbon atoms and isstraight, branched, or cyclic. Examples of such groups include, but arenot limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy,iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.

The term “(C₆ to C₁₄) aryl”, as used herein, means a group derived froman aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examplesof such groups include, but are not limited to, phenyl or naphthyl. Theterms “Ph” and “phenyl,” as used herein, mean a —C₆H₅ group. The term“benzyl,” as used herein, means a —CH₂C₆H₅ group.

“(C₂ to C₉) heteroaryl”, as used herein, means an aromatic heterocyclicgroup having a total of from 5 to 10 atoms in its ring, and containingfrom 2 to 9 carbon atoms and from one to four heteroatoms eachindependently selected from O, S and N, and with the proviso that thering of said group does not contain two adjacent O atoms or two adjacentS atoms. The heterocyclic groups include benzo-fused ring systems.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The C₂ to C₉ heteroaryl groups may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached).

“(C₂ to C₉) cycloheteroalkyl”, as used herein, means a non-aromatic,monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic grouphaving a total of from 4 to 13 atoms in its ring system, and containingfrom 2 to 9 carbon atoms and from 1 to 4 heteroatoms each independentlyselected from O, S and N, and with the proviso that the ring of saidgroup does not contain two adjacent O atoms or two adjacent S atoms.Furthermore, such C₂ to C₉ cycloheteroalkyl groups may contain an oxosubstituent at any available atom that will result in a stable compound.For example, such a group may contain an oxo atom at an available carbonor nitrogen atom. Such a group may contain more than one oxo substituentif chemically feasible. In addition, it is to be understood that whensuch a C₂ to C₉ cycloheteroalkyl group contains a sulfur atom, saidsulfur atom may be oxidized with one or two oxygen atoms to affordeither a sulfoxide or sulfone. An example of a 4 memberedcycloheteroalkyl group is azetidinyl (derived from azetidine). Anexample of a 5 membered cycloheteroalkyl group is pyrrolidinyl. Anexample of a 6 membered cycloheteroalkyl group is piperidinyl. Anexample of a 9 membered cycloheteroalkyl group is indolinyl. An exampleof a 10 membered cycloheteroalkyl group is 4H-quinolizinyl. Furtherexamples of such C₂ to C₉ cycloheteroalkyl groups include, but are notlimited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholine, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, azabicyclo[4.1.0]heptanyl,3H-indolyl quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl.

The term “(C₃ to C₁₀) cycloalkyl group” means a saturated, monocyclic,fused, spirocyclic, or polycyclic ring structure having a total of from3 to 10 carbon ring atoms. Examples of such groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptyl, and adamantyl.

The term “spirocyclic” as used herein has its conventional meaning, thatis, any compound containing two or more rings wherein two of the ringshave one ring carbon in common. The rings of a spirocyclic compound, asherein defined, independently have 3 to 20 ring atoms. Preferably, theyhave 3 to 10 ring atoms. Non-limiting examples of a spirocyclic compoundinclude spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

The term “(C₅ to C₈) cycloalkenyl” means an unsaturated, monocyclic,fused, spirocyclic ring structures having a total of from 5 to 8 carbonring atoms. Examples of such groups include, but not limited to,cyclopentenyl, cyclohexenyl.

The term cyano” refers to a —C≡N group.

An “aldehyde” group refers to a carbonyl group where R is hydrogen.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl group,as defined herein.

An “alkoxycarbonyl” refers to a —C(O)OR.

An “alkylaminoalkyl” group refers to an -alkyl-NR-alkyl group.

An “alkylsulfonyl” group refer to a —SO₂alkyl.

An “amino” group refers to an —NH₂ or an —NRR′group.

An “aminoalkyl” group refers to an -alky-NRR′ group.

An “aminocarbonyl” refers to a —C(O)NRR′.

An “arylalkyl” group refers to -alkylaryl, where alkyl and aryl aredefined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

An “aryloxycarbonyl” refers to —C(O)Oaryl.

An “arylsulfonyl” group refers to a —SO₂aryl.

A “C-amido” group refers to a —C(O)NRR′ group.

A “carbonyl” group refers to a —C(O)R.

A “C-carboxyl” group refers to a —C(O)OR groups.

A “carboxylic acid” group refers to a C-carboxyl group in which R ishydrogen.

A “cyano” group refers to a —CN group.

A “dialkylamionalkyl” group refers to an -(alkyl)N(alkyl)₂ group.

A “halo” or “halogen” group refers to fluorine, chlorine, bromine oriodine.

A “heteroalicycloxy” group refers to a heteroalicyclic-O group withheteroalicyclic as defined herein.

A “heteroaryloxyl” group refers to a heteroaryl-O group with heteroarylas defined herein.

A “hydroxy” group refers to an —OH group.

An “N-amido” group refers to a —R′C(O)NR group.

An “N-carbamyl” group refers to a —ROC(O)NR-group.

A “nitro” group refers to a —NO₂ group.

An “N-Sulfonamido” group refers to a —NR—S(O)₂R group.

An “N-thiocarbamyl” group refers to a ROC(S)NR′ group.

An “O-carbamyl” group refers to a —OC(O)NRR′ group.

An “O-carboxyl” group refers to a RC(O)O group.

An “O-thiocarbamyl” group refers to a —OC(S)NRR′ group.

An “oxo” group refers to a carbonyl moiety such that alkyl substitutedby oxo refers to a ketone group.

A “perfluoroalkyl group” refers to an alkyl group where all of thehydrogen atoms have been replaced with fluorine atoms.

A “phosphonyl” group refers to a —P(O)(OR)₂ group.

A “silyl” group refers to a —Si(R)₃ group.

An “S-sulfonamido” group refers to a —S(O)₂NR-group.

A “sulfinyl” group refers to a —S(O)R group.

A “sulfonyl” group refers to a —S(O)₂R group.

A “thiocarbonyl” group refers to a —C(═S)—R group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(O) group, where Z ishalogen.

A “trihalomethanesulfonamido” group refers to a Z₃CS(O)₂NR-group.

A “trihalomethanesulfonyl” group refers to a Z₃CS(O)₂ group.

A “trihalomethyl” group refers to a —CZ₃ group.

A “C-carboxyl” group refers to a —C(O)OR groups.

The term “substituted,” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted,” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. It is to be understood that in the compounds of thepresent invention when a group is said to be “unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all theatoms in the compound, the remaining valencies on such a group arefilled by hydrogen. For example, if a C₆ aryl group, also called“phenyl” herein, is substituted with one additional substituent, one ofordinary skill in the art would understand that such a group has 4 openpositions left on carbon atoms of the C₆ aryl ring (6 initial positions,minus one to which the remainder of the compound of the presentinvention is bonded, minus an additional substituent, to leave 4). Insuch cases, the remaining 4 carbon atoms are each bound to one hydrogenatom to fill their valencies. Similarly, if a C₆ aryl group in thepresent compounds is said to be “disubstituted,” one of ordinary skillin the art would understand it to mean that the C₆ aryl has 3 carbonatoms remaining that are unsubstituted. Those three unsubstituted carbonatoms are each bound to one hydrogen atom to fill their valencies.

The term “solvate,” is used to describe a molecular complex betweencompounds of the present invention and solvent molecules. Examples ofsolvates include, but are not limited to, compounds of the invention incombination water, isopropanol, ethanol, methanol, dimethylsulfoxide(DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.The term “hydrate” can be used when said solvent is water. It isspecifically contemplated that in the present invention one solventmolecule can be associated with one molecule of the compounds of thepresent invention, such as a hydrate. Furthermore, it is specificallycontemplated that in the present invention, more than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a dihydrate. Additionally, it is specificallycontemplated that in the present invention less than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a hemihydrate. Furthermore, solvates of thepresent invention are contemplated as solvates of compounds of thepresent invention that retain the biological effectiveness of thenon-hydrate form of the compounds.

The term “pharmaceutically acceptable salt,” as used herein, means asalt of a compound of the present invention that retains the biologicaleffectiveness of the free acids and bases of the specified derivativeand that is not biologically or otherwise undesirable.

The term “pharmaceutically acceptable formulation,” as used herein,means a combination of a compound of the invention, or a salt or solvatethereof, and a carrier, diluent, and/or excipient(s) that are compatiblewith a compound of the present invention, and is not deleterious to therecipient thereof. Pharmaceutical formulations can be prepared byprocedures known to those of ordinary skill in the art. For example, thecompounds of the present invention can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,and the like. Examples of excipients, diluents, and carriers that aresuitable for such formulations include the following: fillers andextenders such as starch, sugars, mannitol, and silicic derivatives;binding agents such as carboxymethyl cellulose and other cellulosederivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizingagents such as glycerol; disintegrating agents such as povidone, sodiumstarch glycolate, sodium carboxymethylcellulose, agar, calciumcarbonate, and sodium bicarbonate; agents for retarding dissolution suchas paraffin; resorption accelerators such as quaternary ammoniumcompounds; surface active agents such as cetyl alcohol, glycerolmonostearate; adsorptive carriers such as kaolin and bentonite; andlubricants such as talc, calcium and magnesium stearate and solidpolyethylene glycols. Final pharmaceutical forms may be pills, tablets,powders, lozenges, saches, cachets, or sterile packaged powders, and thelike, depending on the type of excipient used. Additionally, it isspecifically contemplated that pharmaceutically acceptable formulationsof the present invention can contain more than one active ingredient.For example, such formulations may contain more than one compoundaccording to the present invention. Alternatively, such formulations maycontain one or more compounds of the present invention and one or moreadditional agents that reduce abnormal cell growth.

The term “PI3-Kα-inhibiting amount” as used herein, refers to the amountof a compound of the present invention, or a salt or solvate thereof,required to inhibit the enzymatic activity of PI3-Kα in vivo, such as ina mammal, or in vitro. The amount of such compounds required to causesuch inhibition can be determined without undue experimentation usingmethods described herein and those known to those of ordinary skill inthe art.

The term “inhibiting PI3-Kα enzyme activity,” as used herein, meansdecreasing the activity or functioning of the PI3-Kα enzyme either invitro or in vivo, such as in a mammal, such as a human, by contactingthe enzyme with a compound of the present invention.

The term “PI3-Kα” as used herein means PI3-Kα, or mutants thereof, orany of the known PI3-Kα isoformic splice variants.

The term “therapeutically effective amount,” as used herein, means anamount of a compound of the present invention, or a salt thereof, that,when administered to a mammal in need of such treatment, is sufficientto effect treatment, as defined herein. Thus, a therapeuticallyeffective amount of a compound of the present invention, or a saltthereof, is a quantity sufficient to modulate or inhibit the activity ofthe PI3-Kα enzyme such that a disease condition that is mediated byactivity of the PI3-Kα enzyme is reduced or alleviated.

The terms “treat”, “treating”, and “treatment” with reference toabnormal cell growth, or to any PI3-Kα mediated disease or condition, ina mammal, particularly a human, include: (i) preventing the disease orcondition from occurring in a subject which may be predisposed to thecondition, such that the treatment constitutes prophylactic treatmentfor the pathologic condition; (ii) modulating or inhibiting the diseaseor condition, i.e., arresting its development; (iii) relieving thedisease or condition, i.e., causing regression of the disease orcondition; or (iv) relieving and/or alleviating the disease or conditionor the symptoms resulting from the disease or condition, e.g., relievingan inflammatory response without addressing the underlying disease orcondition. With regard to abnormal cell growth, such as cancer, theseterms simply mean that the life expectancy of an individual affectedwith abnormal cell growth will be increased or that one or more of thesymptoms of the disease will be reduced.

Unless indicated otherwise, all references herein to the inventivecompounds include references to salts, solvates, and complexes thereof,including polymorphs, stereoisomers, tautomers, and isotopically labeledversions thereof. For example, compounds of the present invention can bepharmaceutically acceptable salts and/or pharmaceutically acceptablesolvates.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition), including the abnormalgrowth of normal cells and the growth of abnormal cells. This includes,but is not limited to, the abnormal growth of: tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or overexpression ofa receptor tyrosine kinase; benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; any tumors that proliferate by receptor tyrosine kinases; anytumors that proliferate by aberrant serine/threonine kinase activation;benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs; tumors, both benignand malignant, expressing an activated Ras oncogene; tumor cells, bothbenign and malignant, in which the Ras protein is activated as a resultof oncogenic mutation in another gene; benign and malignant cells ofother proliferative diseases in which aberrant Ras activation occurs.Examples of such benign proliferative diseases are psoriasis, benignprostatic hypertrophy, human papilloma virus (HPV), and restinosis.“Abnormal cell growth” also refers to and includes the abnormal growthof cells, both benign and malignant, resulting from activity of theenzyme farnesyl protein transferase.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

The term “stereoisomers” refers to compounds that have identicalchemical constitution, but differ with regard to the arrangement oftheir atoms or groups in space. In particular, the term “enantiomers”refers to two stereoisomers of a compound that are non-superimposablemirror images of one another. The terms “racemic” or “racemic mixture,”as used herein, refer to a 1:1 mixture of enantiomers of a particularcompound. The term “diastereomers”, on the other hand, refers to therelationship between a pair of stereoisomers that comprise two or moreasymmetric centers and are not mirror images of one another.

In accordance with a convention used in the art, the symbol

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure. In accordance with another convention, in some structuralformulae herein the carbon atoms and their bound hydrogen atoms are notexplicitly depicted, e.g.,

represents a methyl group,

represents an ethyl group,

represents a cyclopentyl group, etc.

The compounds of the present invention may have asymmetric carbon atoms.The carbon-carbon bonds of the compounds of the present invention may bedepicted herein using a solid line (

), a solid wedge

, or a dotted wedge

. The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of the invention maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof the present invention can exist as enantiomers and diastereomers oras racemates and mixtures thereof. The use of a solid line to depictbonds to one or more asymmetric carbon atoms in a compound of theinvention and the use of a solid or dotted wedge to depict bonds toother asymmetric carbon atoms in the same compound is meant to indicatethat a mixture of diastereomers is present.

If a group, as for example, “R” is depicted as “floating” on a ringsystem A in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed. A ring system A may be, for example, but notlimited to aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclylor a fused ring system.

If a group “R” is depicted as “floating” on a ring system A containingsaturated carbons, than “z” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen the ring A;then, unless otherwise defined, where the resulting structure is stable,two “R's” may reside on the same carbon. For example, when R is a methylgroup, there can exist a germinal dimethyl on a carbon of the ring A. Inanother example, two “R's” on the same carbon, including that carbon,may form a ring, thus creating a spirocyclic ring (a “spirocyclylgroup”).

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the reacemate using, for example, chiral highpressure liquid chromatography (HPLC). Alternatively, the racemate (or aracemic precursor) may be reacted with a suitable optically activecompound, for example, an alcohol, or, in the case where the compoundcontains an acidic or basic moiety, an acid or base such as tartaricacid or 1-phenylethylamine. The resulting diastereomeric mixture may beseparated by chromatography and/or fractional crystallization and one orboth of the diastereoisomers converted to the corresponding pureenantiomer(s) by means well known to one skilled in the art. Chiralcompounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture. Stereoisomeric conglomerates may be separated byconventional techniques known to those skilled in the art. See, e.g.“Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York,1994), the disclosure of which is incorporated herein by reference inits entirety.

Where a compound of the invention contains an alkenyl or alkenylenegroup, geometric cis/trans (or Z/E) isomers are possible. Where thecompound contains, for example, a keto or oxime group or an aromaticmoiety, tautomeric isomerism (‘tautomerism’) can occur. Examples oftautomerism include keto and enol tautomers. A single compound mayexhibit more than one type of isomerism. Included within the scope ofthe invention are all stereoisomers, geometric isomers and tautomericforms of the inventive compounds, including compounds exhibiting morethan one type of isomerism, and mixtures of one or more thereof.Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

The compounds of the present invention may be administered as prodrugs.Thus certain derivatives of compounds of Formula (I), which may havelittle or no pharmacological activity themselves can, when administeredto a mammal, be converted into a compound of Formula (I) having thedesired activity, for example, by hydrolytic cleavage. Such derivativesare referred to as “prodrugs”. Prodrugs can, for example, be produced byreplacing appropriate functionalities present in the compound of Formula(I) with certain moieties known to those skilled in the art. See, e.g.“Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (THiguchi and W Stella) and “Bioreversible Carriers in Drug Design”,Pergamon Press, 1987 (ed. E B Roche, American PharmaceuticalAssociation), the disclosures of which are incorporated herein byreference in their entireties. Some examples of such prodrugs include:an ester moiety in the place of a carboxylic acid functional group; anether moiety or an amide moiety in place of an alcohol functional group;and an amide moiety in place of a primary or secondary amino functionalgroup. For example, the compound shown as Example 31 below is oneexample of where the hydrogen in an alcohol moiety is replaced by anamide functional group. Further examples of replacement groups are knownto those of skill in the art. See, e.g. “Design of Prodrugs” by HBundgaard (Elsevier, 1985), the disclosure of which is incorporatedherein by reference in its entirety. It is also possible that certaincompounds of Formula (I) may themselves act as prodrugs of othercompounds of Formula (I).

Salts of the present invention can be prepared according to methodsknown to those of skill in the art. Examples of salts include, but arenot limited to, acetate, acrylate, benzenesulfonate, benzoate (such aschlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, andmethoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate,bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate,chloride, caproate, caprylate, clavulanate, citrate, decanoate,dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate,esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate,glutamate, glycollate, glycollylarsanilate, heptanoate,hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate,lactate, lactobionate, laurate, malate, maleate, malonate, mandelate,mesylate, metaphosphate, methane-sulfonate, methylsulfate,monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phenylacetates, phenyl butyrate,phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate,propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate,salicylate, stearate, subacetate, suberate, succinate, sulfate,sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode,and valerate salts.

The compounds of the present invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention can beprepared by treating the base compound with a substantially equivalentamount of the selected mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or ethanol.Upon evaporation of the solvent, the desired solid salt is obtained. Thedesired acid salt can also be precipitated from a solution of the freebase in an organic solvent by adding an appropriate mineral or organicacid to the solution.

Those compounds of the present invention that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

If the inventive compound is a base, the desired salt may be prepared byany suitable method available in the art, for example, treatment of thefree base with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronicacid or galacturonic acid, an alpha-hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired salt may be preparedby any suitable method, for example, treatment of the free acid with aninorganic or organic base, such as an amine (primary, secondary ortertiary), an alkali metal hydroxide or alkaline earth metal hydroxide,or the like. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds, agents and salts may exist indifferent crystal or polymorphic forms, all of which are intended to bewithin the scope of the present invention and specified formulas.

The invention also includes isotopically-labeled compounds of theinvention, wherein one or more atoms is replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopessuitable for inclusion in the compounds of the invention includeisotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³Iand ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, ³H, andcarbon-14, ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium, ²H, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The compounds of the present invention may be formulated intopharmaceutical compositions as described below in any pharmaceuticalform recognizable to the skilled artisan as being suitable.Pharmaceutical compositions of the invention comprise a therapeuticallyeffective amount of at least one compound of the present invention andan inert, pharmaceutically acceptable carrier or diluent.

To treat or prevent diseases or conditions mediated by PI3-Kα, apharmaceutical composition of the invention is administered in asuitable formulation prepared by combining a therapeutically effectiveamount (i.e., a PI3-Kα modulating, regulating, or inhibiting amounteffective to achieve therapeutic efficacy) of at least one compound ofthe present invention (as an active ingredient) with one or morepharmaceutically suitable carriers, which may be selected, for example,from diluents, excipients and auxiliaries that facilitate processing ofthe active compounds into the final pharmaceutical preparations.

The pharmaceutical carriers employed may be either solid or liquid.Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryliquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the inventive compositions may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate or the like. Furtheradditives or excipients may be added to achieve the desired formulationproperties. For example, a bioavailability enhancer, such as Labrasol,Gelucire or the like, or formulator, such as CMC(carboxy-methylcellulose), PG (propyleneglycol), or PEG(polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle thatprotects active ingredients from light, moisture and oxidation, may beadded, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form, or formed into a trocheor lozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of syrup, emulsion, soft gelatin capsule,sterile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension. If a semi-solid carrier is used, thepreparation may be in the form of hard and soft gelatin capsuleformulations. The inventive compositions are prepared in unit-dosageform appropriate for the mode of administration, e.g. parenteral or oraladministration.

To obtain a stable water-soluble dose form, a salt of a compound of thepresent invention may be dissolved in an aqueous solution of an organicor inorganic acid, such as a 0.3 M solution of succinic acid or citricacid. If a soluble salt form is not available, the agent may bedissolved in a suitable co-solvent or combinations of co-solvents.Examples of suitable co-solvents include alcohol, propylene glycol,polyethylene glycol 300, polysorbate 80, glycerin and the like inconcentrations ranging from 0 to 60% of the total volume. In anexemplary embodiment, a compound of the present invention is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

Proper formulation is dependent upon the route of administrationselected. For injection, the agents of the compounds of the presentinvention may be formulated into aqueous solutions, preferably inphysiologically compatible buffers such as Hanks solution, Ringerssolution, or physiological saline buffer. For transmucosaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers known inthe art. Such carriers enable the compounds of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. Pharmaceutical preparations for oral use can be obtainedusing a solid excipient in admixture with the active ingredient (agent),optionally grinding the resulting mixture, and processing the mixture ofgranules after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include: fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; and cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds of thepresent invention may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion-exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt. A pharmaceuticalcarrier for hydrophobic compounds is a co-solvent system comprisingbenzyl alcohol, a non-polar surfactant, a water-miscible organicpolymer, and an aqueous phase. The co-solvent system may be a VPDco-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution.This co-solvent system dissolves hydrophobic compounds well, and itselfproduces low toxicity upon systemic administration. The proportions of aco-solvent system may be suitably varied without destroying itssolubility and toxicity characteristics. Furthermore, the identity ofthe co-solvent components may be varied: for example, other low-toxicitynon-polar surfactants may be used instead of polysorbate 80; thefraction size of polyethylene glycol may be varied; other biocompatiblepolymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone;and other sugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity due to the toxic nature of DMSO.Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. These carriers and excipients mayprovide marked improvement in the bioavailability of poorly solubledrugs. Examples of such carriers or excipients include calciumcarbonate, calcium phosphate, sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols. Furthermore,additives or excipients such as Gelucire®, Capryol®, Labrafil®,Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like maybe used.

Further, the pharmaceutical composition may be incorporated into a skinpatch for delivery of the drug directly onto the skin.

It will be appreciated that the actual dosages of the agents of thisinvention will vary according to the particular agent being used, theparticular composition formulated, the mode of administration, and theparticular site, host, and disease being treated. Those skilled in theart using conventional dosage-determination tests in view of theexperimental data for a given compound may ascertain optimal dosages fora given set of conditions. For oral administration, an exemplary dailydose generally employed will be from about 0.001 to about 1000 mg/kg ofbody weight, with courses of treatment repeated at appropriateintervals.

Furthermore, the pharmaceutically acceptable formulations of the presentinvention may contain a compound of the present invention, or a salt orsolvate thereof, in an amount of about 10 mg to about 2000 mg, or fromabout 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, orfrom about 10 mg to about 750 mg, or from about 10 mg to about 500 mg,or from about 25 mg to about 500 mg, or from about 50 to about 500 mg,or from about 100 mg to about 500 mg.

Additionally, the pharmaceutically acceptable formulations of thepresent invention may contain a compound of the present invention, or asalt or solvate thereof, in an amount from about 0.5 w/w % to about 95w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % toabout 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.

The compounds of the present invention, or salts or solvates thereof,may be administered to a mammal suffering from abnormal cell growth,such as a human, either alone or as part of a pharmaceuticallyacceptable formulation, once a day, twice a day, three times a day, orfour times a day, or even more frequently.

Those of ordinary skill in the art will understand that with respect tothe compounds of the present invention, the particular pharmaceuticalformulation, the dosage, and the number of doses given per day to amammal requiring such treatment, are all choices within the knowledge ofone of ordinary skill in the art and can be determined without undueexperimentation.

The compounds of the present invention are useful for modulating orinhibiting PI3-Kα activity. Accordingly, these compounds are useful forthe prevention and/or treatment of disease states associated withabnormal cell growth such as cancer, alone or in combination with otheranti-cancer agents.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the Formula (I), as definedabove, or a salt or solvate thereof, that is effective in treatingabnormal cell growth.

In one embodiment of this method, the abnormal cell growth is cancer,including, but not limited to, mesothelioma, hepatobilliary (hepatic andbilliary duct), a primary or secondary CNS tumor, a primary or secondarybrain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, gastrointestinal (gastric,colorectal, and duodenal), breast cancer, uterine cancer, carcinoma ofthe fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'sDisease, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, prostate cancer, testicularcancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma,fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one ormore of the foregoing cancers.

In one embodiment of the present invention the cancer is selected fromlung cancer (NSCLC and SCLC), cancer of the head or neck, ovariancancer, colon cancer, rectal cancer, cancer of the anal region, stomachcancer, breast cancer, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma,spinal axis tumors, or a combination of one or more of the foregoingcancers.

In another embodiment of the present invention the cancer is selectedfrom lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectalcancer, cancer of the anal region, or a combination of one or more ofthe foregoing cancers.

In another embodiment of the present invention the cancer is selectedfrom lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectalcancer, or a combination of one or more of the foregoing cancers.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of the present invention, or a salt or solvatethereof, that is effective in treating abnormal cell growth incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

In one embodiment of the present invention the anti-tumor agent used inconjunction with a compound of the present invention and pharmaceuticalcompositions described herein is an anti-angiogenesis agent, kinaseinhibitor, pan kinase inhibitor or growth factor inhibitor. Preferredpan kinase inhibitors include Sutent™ (sunitinib), described in U.S.Pat. No. 6,573,293 (Pfizer, Inc, NY, USA). Anti-angiogenesis agents,include but are not limited to the following agents, such as EGFinhibitors, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2inhibitors, IGF1R inhibitors, COX-II (cyclooxygenase II) inhibitors,MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9(matrix-metalloprotienase 9) inhibitors.

Preferred VEGF inhibitors, include for example, Avastin (bevacizumab),an anti-VEGF monoclonal antibody of Genentech, Inc. of South SanFrancisco, Calif. Additional VEGF inhibitors include CP-547,632 (PfizerInc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788(Novartis), AZD-2171, VEGF Trap (Regeneron/Aventis), Vatalanib (alsoknown as PTK-787, ZK-222584: Novartis & Schering AG), Macugen(pegaptanib octasodium, NX-1838, EYE-001, Pfizer Inc./Gilead/Eyetech),IM862 (Cytran Inc. of Kirkland, Wash., USA); and angiozyme, a syntheticribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.)and combinations thereof.

VEGF inhibitors useful in the practice of the present invention aredescribed in U.S. Pat. Nos. 6,534,524 and 6,235,764, both of which areincorporated in their entirety for all purposes. Additional VEGFinhibitors are described in, for example in WO 99/24440, in WO 95/21613,WO 99/61422, U.S. Pat. No. 5,834,504, WO 98/50356, U.S. Pat. No.5,883,113 U.S. Pat. No. 5,886,020, U.S. Pat. No. 5,792,783, U.S. Pat.No. 6,653,308, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO98/02438, WO 99/16755, and WO 98/02437, all of which are hereinincorporated by reference in their entirety.

Other anti-angiogenic compounds include acitretin, fenretinide,thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,combretastatin A-4, endostatin, halofuginone, rebimastat, removab,Revlimid, squalamine, ukrain, Vitaxin and combinations thereof.

Other antiproliferative agents that may be used in combination with thecompounds of the present invention include inhibitors of the enzymefarnesyl protein transferase and inhibitors of the receptor tyrosinekinase PDGFr, including the compounds disclosed and claimed in thefollowing: U.S. Pat. No. 6,080,769; U.S. Pat. No. 6,194,438; U.S. Pat.No. 6,258,824; U.S. Pat. No. 6,586,447; U.S. Pat. No. 6,071,935; U.S.Pat. No. 6,495,564; and U.S. Pat. No. 6,150,377; U.S. Pat. No.6,596,735; U.S. Pat. No. 6,479,513; WO 01/40217; U.S. 2003-0166675. Eachof the foregoing patents and patent applications is herein incorporatedby reference in their entirety.

PDGRr inhibitors include but are not limited to those disclosed ininternational patent application publication numbers WO01/40217 andWO2004/020431, the contents of which are incorporated in their entiretyfor all purposes. Preferred PDGFr inhibitors include Pfizer's CP-673,451and CP-868,596 and its salts.

Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and itssalts). GARF inhibitors useful in the practice of the present inventionare disclosed in U.S. Pat. No. 5,608,082 which is incorporated in itsentirety for all purposes.

Examples of useful COX-II inhibitors which can be used in conjunctionwith a compound of Formula (I) and pharmaceutical compositions disclosedherein include CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963,MK-663 (etoricoxib), COX-189 (Lumiracoxib), BMS 347070, RS 57067,NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381,4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole,2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoyl phenyl)-1H-pyrrole, T-614,JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).Additionally, COX-II inhibitors are disclosed in U.S. PatentApplications US 2005-0148627 and US 2005-0148777, the contents of whichare incorporated in their entirety for all purposes.

In a particular embodiment the anti-tumor agent is celecoxib (U.S. Pat.No. 5,466,823), valdecoxib (U.S. Pat. No. 5,633,272), parecoxib (U.S.Pat. No. 5,932,598), deracoxib (U.S. Pat. No. 5,521,207), SD-8381 (U.S.Pat. No. 6,034,256, Example 175), ABT-963 (WO 2002/24719), rofecoxib(CAS No. 162011-90-7), MK-663 (or etoricoxib) as disclosed in WO1998/03484, COX-189 (Lumiracoxib) as disclosed in WO 1999/11605,BMS-347070 (U.S. Pat. No. 6,180,651), NS-398 (CAS 123653-11-2), RS 57067(CAS 17932-91-3),4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole,2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, ormeloxicam.

Other useful inhibitors as anti-tumor agents used in combination with acompound of the present invention and pharmaceutical compositionsdisclosed herein include aspirin, and non-steroidal anti-inflammatorydrugs (NSAIDs) which inhibit the enzyme that makes prostaglandins(cyclooxygenase I and II), resulting in lower levels of prostaglandins,include but are not limited to the following, Salsalate (Amigesic),Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Orudis),Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn),Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril),Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin(Daypro) and combinations thereof.

Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen(Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinationsthereof.

Targeted agents used in combination with a compound of the presentinvention and pharmaceutical compositions disclosed herein include EGFrinhibitors such as Iressa (gefitinib, AstraZeneca), Tarceva (erlotinibor OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, ImclonePharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc. andAbgenix Inc.), HR3 (Cuban Government), IgA antibodies (University ofErlangen-Nuremberg), TP-38 (IVAX), EGFR fusion protein, EGF-vaccine,anti-EGFr immunoliposomes (Hermes Biosciences Inc.) and combinationsthereof. Preferred EGFr inhibitors include Iressa, Erbitux, Tarceva andcombinations thereof.

Other anti-tumor agents include those selected from pan erb receptorinhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer,Inc.), CI-1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab,Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165(Takeda), GW-572016 (Ionafarnib, GlaxoSmithKline), GW-282974(GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis), dHER2 (HER2Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon),anti-HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.IgG3(Agensys), AS HER2 (Research Institute for Rad Biology & Medicine),trifunctional bispecific antibodies (University of Munich) and mABAR-209 (Aronex Pharmaceuticals Inc) and mAB 2B-1 (Chiron) andcombinations thereof.

Preferred erb selective anti-tumor agents include Herceptin, TAK-165,CP-724,714, ABX-EGF, HER3 and combinations thereof. Preferred pan erbbreceptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg andcombinations thereof.

Additional erbB2 inhibitors include those disclosed in WO 98/02434, WO99/35146, WO 99/35132, WO 98/02437, WO 97/13760, WO 95/19970, U.S. Pat.No. 5,587,458, and U.S. Pat. No. 5,877,305, each of which is hereinincorporated by reference in its entirety. ErbB2 receptor inhibitorsuseful in the present invention are also disclosed in U.S. Pat. Nos.6,465,449, and 6,284,764, and in WO 2001/98277 each of which are hereinincorporated by reference in their entirety.

Additionally, other anti-tumor agents may be selected from the followingagents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen,Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar(Corixa/GlaxoSmithKline), Abarelix, Alimta, EPO 906 (Novartis),discodermolide (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna),enzastaurin (Eli Lilly), Combrestatin A4P (Oxigene), ZD-6126(AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacel), AVE-8062(Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar(temozolomide, Schering Plough) and Revilimd (Celegene) and combinationsthereof.

Other anti-tumor agents may be selected from the following agents, CyPat(cyproterone acetate), Histerelin (histrelin acetate), Plenaixis(abarelix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid(Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel),Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamatepaclitaxel), Targetin (bexarotine) and combinations thereof.

Additionally, other anti-tumor agents may be selected from the followingagents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941),Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin,Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase(ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) andcombinations thereof.

Further anti-tumor agents may be selected from the following agents,CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinationsthereof. Additional anti-tumor agents may be selected from the followingagents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof.Additional anti-tumor agents may be selected from the following agents,Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof.Additional anti-tumor agents may be selected from the following agents,RSR13 (efaproxiral), Cotara (131 I chTNT 1/b), NBI-3001 (IL-4) andcombinations thereof. Additional anti-tumor agents may be selected fromthe following agents, Canvaxin, GMK vaccine, PEG Interon A, Taxoprexin(DHA/paciltaxel), and combinations thereof.

Other anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901,Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2inhibitor BMS-387,032, Pfizer's CDK inhibitor PD0332991 andAstraZeneca's AXD-5438, and combinations thereof.

Additionally, mTOR inhibitors may also be utilized such as CCI-779(Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573(Ariad), HDAC inhibitors, SAHA (Merck Inc./Aton Pharmaceuticals) andcombinations thereof. Additional anti-tumor agents include aurora 2inhibitor VX-680 (Vertex), and Chk1/2 inhibitor XL844 (Exilixis).

The following cytotoxic agents, e.g., one or more selected from thegroup consisting of epirubicin (Ellence), docetaxel (Taxotere),paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinibmesylate (Gleevec), and combinations thereof, may be used in combinationwith a compound of the present invention and pharmaceutical compositionsdisclosed herein.

The invention also contemplates the use of the compounds of the presentinvention together with hormonal therapy, including but not limited to,exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin,TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin(Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane,tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex(AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.

The invention also relates to the use of the compounds of the presentinvention together with hormonal therapy agents such as anti-estrogensincluding, but not limited to fulvestrant, toremifene, raloxifene,lasofoxifene, letrozole (Femara, Novartis), anti-androgens such asbicalutamide, flutamide, mifepristone, nilutamide, Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide,bicalutamide) and combinations thereof.

Further, the invention provides a compound of the present inventionalone or in combination with one or more supportive care products, e.g.,a product selected from the group consisting of Filgrastim (Neupogen),ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinationsthereof.

Particularly preferred cytotoxic agents include Camptosar, Erbitux,Iressa, Gleevec, Taxotere and combinations thereof.

The following topoisomerase I inhibitors may be utilized as anti-tumoragents: camptothecin; irinotecan HCl (Camptosar); edotecarin; orathecin(Supergen); exatecan (Daiichi); BN-80915 (Roche); and combinationsthereof. Particularly preferred toposimerase II inhibitors includeepirubicin (Ellence).

Alkylating agents include, but are not limited to, nitrogen mustardN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,mitobronitol, carboquone, thiotepa, ranimustine, nimustine,temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin,bendamustine, carmustine, estramustine, fotemustine, glufosfamide,ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinatedalkylating compounds include but are not limited to, cisplatin,Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin(oxaliplatin, Sanofi) or satrplatin and combinations thereof.Particularly preferred alkylating agents include Eloxatin (oxaliplatin).

Antimetabolites include but are not limited to, methotrexate,6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) aloneor in combination with leucovorin, tegafur, UFT, doxifluridine,carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta(premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, Eli Lilly),fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine,decitabine, eflornithine, ethynylcytidine, cytosine arabinoside,hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate,disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine,trimetrexate, vidarabine, vincristine, vinorelbine; or for example, oneof the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid and combinations thereof.

Antibiotics include intercalating antibiotics and include, but are notlimited to: aclarubicin, actinomycin D, amrubicin, annamycin,adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin,epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, valrubicin, zinostatin and combinations thereof.

Plant derived anti-tumor substances include for example those selectedfrom mitotic inhibitors, for example vinblastine, docetaxel (Taxotere),paclitaxel and combinations thereof.

Cytotoxic topoisomerase inhibiting agents include one or more agentsselected from the group consisting of aclarubicn, amonafide, belotecan,camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan,irinotecan HCl (Camptosar), edotecarin, epirubicin (Ellence), etoposide,exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone,rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and combinationsthereof.

Preferred cytotoxic topoisomerase inhibiting agents include one or moreagents selected from the group consisting of camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan HCl (Camptosar),edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, andcombinations thereof.

Immunologicals include interferons and numerous other immune enhancingagents. Interferons include interferon alpha, interferon alpha-2a,interferon, alpha-2b, interferon beta, interferon gamma-1a, interferongamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof.Other agents include filgrastim, lentinan, sizofilan, TheraCys,ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine,daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod,lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin,tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab,pemtumomab (Y-muHMFG1), Provenge (Dendreon) and combinations thereof.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity. Such agents include krestin, lentinan, sizofuran, picibanil,ubenimex and combinations thereof.

Other anticancer agents that can be used in combination with a compoundof the present invention include alitretinoin, ampligen, atrasentanbexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride,fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase,procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,tazarotne, Telcyta (TLK-286, Telik Inc.), Velcade (bortemazib,Millenium), tretinoin, and combinations thereof.

Platinum-coordinated compounds include but are not limited to,cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinationsthereof.

Camptothecin derivatives include but are not limited to camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38,edotecarin, topotecan and combinations thereof. Other antitumor agentsinclude mitoxantrone, 1-asparaginase, procarbazine, dacarbazine,hydroxycarbamide, pentostatin, tretinoin and combinations thereof.

Anti-tumor agents capable of enhancing antitumor immune responses, suchas CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agentscapable of blocking CTLA4 may also be utilized, such as MDX-010(Medarex) and CTLA4 compounds disclosed in U.S. Pat. No. 6,682,736; andanti-proliferative agents such as other farnesyl protein transferaseinhibitors, for example the farnesyl protein transferase inhibitors.Additionally, specific CTLA4 antibodies that can be used in combinationwith compounds of the present invention include those disclosed in U.S.Pat. Nos. 6,682,736 and 6,682,736 both of which are herein incorporatedby reference in their entirety.

Specific IGF1R antibodies that can be used in the combination methods ofthe present invention include those disclosed in WO 2002/053596, whichis herein incorporated by reference in its entirety.

Specific CD40 antibodies that can be used in the present inventioninclude those disclosed in WO 2003/040170 which is herein incorporatedby reference in its entirety. Gene therapy agents may also be employedas anti-tumor agents such as TNFerade (GeneVec), which express TNFalphain response to radiotherapy.

In one embodiment of the present invention statins may be used incombination with a compound of the present invention and pharmaceuticalcompositions thereof. Statins (HMG-CoA reducatase inhibitors) may beselected from the group consisting of Atorvastatin (Lipitor™, PfizerInc.), Provastatin (Pravachol™, Bristol-Myers Squibb), Lovastatin(Mevacor™, Merck Inc.), Simvastatin (Zocor™, Merck Inc.), Fluvastatin(Lescol™, Novartis), Cerivastatin (Baycol™, Bayer), Rosuvastatin(Crestor™, AstraZeneca), Lovostatin and Niacin (Advicor™, KosPharmaceuticals), derivatives and combinations thereof.

In a preferred embodiment the statin is selected from the groupconsisting of Atovorstatin and Lovastatin, derivatives and combinationsthereof. Other agents useful as anti-tumor agents include Caduet.

In the following Preparations and Examples, “Ac” means acetyl, “Me”means methyl, “Et” means ethyl, “Ph” means phenyl, “BOC”, “Boc” or “boc”means N-tert-butoxycarbonyl, “DCM” (CH₂Cl₂) means methylene chloride,“DIPEA” or “DIEA” means diisopropyl ethyl amine, “DMA” meansN,N-dimethylacetamide, “DMF” means N—N-dimethyl formamide, “DMSO” meansdimethylsulfoxide, “DPPP” means 1,3-bis(diphenylphosphino)propane,“HOAc” means acetic acid, “IPA” means isopropyl alcohol, “NMP” means1-methyl 2-pyrrolidinone, “TEA” means triethyl amine, “TFA” meanstrifluoroacetic acid, “DCM” means dichloromethane, “EtOAc” means ethylacetate, “MgSO₄” means magnesium sulphate, “Na₂SO₄” means sodiumsulphate, “MeOH” means methanol, “Et₂O” means diethyl ether, “EtOH”means ethanol, “H₂O” means water, “HCl” means hydrochloric acid, “POCl₃”means phosphorus oxychloride, “K₂CO₃” means potassium carbonate, “THF”means tetrahydrofuran, “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene,“LiHMDS” or “LHMDS” means lithium hexamethyldisilazide, “TBME” or “MTBE”means tert-butyl methyl ether, “LDA” means lithium diisopropylamide, “N”means Normal, “M” means molar, “mL” means millilitre, “mmol” meansmillimoles, “μmol” means micromoles, “eq.” means equivalent, “° C.”means degrees Celsius, “Pa” means pascals.

Methods of Preparation

Compounds of the present invention may be prepared using the reactionroutes and synthetic schemes described below, employing the techniquesavailable in the art using starting materials that are readilyavailable. The preparation of certain embodiments of the presentinvention is described in detail in the following examples, but those ofordinary skill in the art will recognize that the preparations describedmay be readily adapted to prepare other embodiments of the presentinvention. For example, the synthesis of non-exemplified compoundsaccording to the invention may be performed by modifications apparent tothose skilled in the art, e.g. by appropriately protecting interferinggroups, by changing to other suitable reagents known in the art, or bymaking routine modifications of reaction conditions. Alternatively,other reactions referred to herein or known in the art will berecognized as having adaptability for preparing other compounds of theinvention.

In one general synthetic process, compounds of the general structurerepresented by 3 are prepared according to Method A.

Compound 1, wherein X is Cl, Br or I and the preparation was describedin WO2005105801, is converted to compound 2 by treatment with an amineof the formula R₁NH₂ in a suitable solvent, for example, dioxane, in thepresence of a base, for example, triethyl amine, at an elevatedtemperature ranging from 40° C. to 220° C. for a period of time rangingfrom a few hours to a few days. Compound 2 is converted to compound 3 bytreatment with boronic acid of the formula R₃—B(OH)₂ or a correspondingboronic ester, following modified Suzuki reaction conditions known tothose skilled in the art.

In another general synthetic process, compounds of the general structurerepresented by 8 are prepared according to Method B.

Compound 4 is converted to compound 5 by reacting with an acrylate esterin the presence of N-cyclohexyl-N-methylcyclohexanamine,tri-tert-butylphosphonium tetrafluoroborate, lithium chloride andtris(dibenzylldeneacetone)dipalladium(0), in a suitable solvent, forexample, 1,4-dioxane at a temperature ranging from 50° C. to 75° C. forhalf of an hour to several days. Compound 5 is converted to compound 6by hydrogenation. Hydrolysis of the ester derivative 6, followed byamide formation, yields compound of formula 8.

In another general synthetic process, compounds of the general structurerepresented by 11 are prepared according to Method C.

Compound 9 is converted to compound 10 by treatment with trimethylborateand butyl lithium in a suitable solvent, for example, THF at lowtemperature ranging from −40° C. to −90° C. Compound 10 is converted tocompound 11 by reacting with R₃—X following Suzuki reaction conditionsknown to those skilled in the art.

In another general synthetic process, compounds of the general structurerepresented by 16 are prepared according to Method D.

Compound 12 is reacted with an alcohol of the formula R₂OH in thepresence of triphenylphosphine and diethyl azodicarboxylate (DEAD) in asuitable solvent, for example, THF at a temperature ranging from room 0°C. to 60° C. to afford compound of formula 13. Compound 13 is convertedto compound 14 by treatment with boronic acid of the formula R₃—B(OH)₂or a corresponding boronic ester, following modified Suzuki reactionconditions known to those skilled in the art. Compound 14 is oxidized toafford compound 15 using reagents such as, for example,m-chloroperbenzoic acid (MCPBA). Treatment of compound 15 with an amineof formula R₁NH₂ affords compound 16.

In another general synthetic process, compounds represented by 21 areprepared according to Method E.

Compound 17 is converted to compound 18 by treatment with R₂X, wherein Xis Cl, Br or I, in the presence of a base, for example, sodium hydride,in a suitable solvent such as, for example, DMF, at a temperatureranging from 25° C. to 100° C. Compound 18 is converted to compound 19by treatment with boronic acid of the formula R₃—B(OH)₂ or acorresponding boronic ester, following Suzuki reaction conditions knownto those skilled in the art. Compound 19 is oxidized to afford compound20 using reagents such as, for example, MCPBA. Treatment of compound 20with an amine of formula R₁NH₂ in a suitable solvent such as, forexample, THF under reflux conditions affords compound of formula 21.

In another general synthetic process, compounds of the general structurerepresented by 28 are prepared according to Method F.

Commercially available compound 22 is converted to compound 23 byreacting with amine of the formula R₂—NH₂ in a suitable solvent such as,for example, dimethylacetamide, in the presence of bases such aspotassium carbonate and diisopropylethyl amine, at elevated temperatureranging from 40° C. to 220° C. for a period of time ranging from a fewhours to a few days. Compound 23 is converted to compound 24 wherein Xis Cl, Br or I by treatment with N-halosuccinamide in a suitable solventsuch as chloroform or carbon tetrachloride, at ambient temperature for aperiod of time ranging from 30 min to a few hours. Compound 24 isconverted to compound 25 by reacting with an acrylate ester in thepresence of tri-o-tolylphosphine, palladium (II) acetate andtriethylamine at an elevated temperature. Compound 25 is converted tocompound 26 by heating the solution of compound 25, thiophenol or KOtBu,and organic bases such as triethylamine and DBU, in a suitable solventsuch as dimethylacetamide at an elevated temperature ranging from 40° C.to 220° C. for a period of time ranging from a few hours to a few days.Compound 26 is converted to compound 27 by treatment withN-halosuccinamide in a suitable solvent such as DMF at ambienttemperature for a period of time ranging from 30 min to a few hours.Compound 27 is then converted to compound 28 by reacting with boronicacid of the formula R₃—B(OH)₂ or a corresponding boronic ester, in thepresence of a base, for example, potassium carbonate, andbis(triphenylphosphine) palladium (II) chloride, in a suitable solventsuch as DMF and water solution, at an elevated temperature ranging from70° C. to 120° C., for a period of time from several hours to a fewdays.

Method F can be used, for example, for preparing compound 28 wherein R₂is an optionally substituted spirocyclic group.

In a glove box, the following was added to a 2.0 mL Personal ChemistryMicrowave reaction tube: one triangular stir bar, the appropriate arylhalide 29 solution in DMF (300 μL, 75 μmol, 1.0 eq., 0.25 M), theappropriate boronic acid or boronic ester in DMF (300 μL, 75 μmol, 1.0eq., 0.25 M), catalyst Pd(PPh₃)₄ in anhydrous THF (300 μL, 3.75 μmol,0.05 eq., 0.0125 M) and K₂CO₃ in degassed DI water (94 μL, 188 μmol, 2.5eq., 2.0 M). The microwave tube was sealed with a septum cap, andoutside the glove box, the reaction mixtures were heated in a PersonalChemistry Microwave Synthesizer for 15 minutes at 130° C. The reactionmixtures were transferred into a 13×100 mm test tube. The microwavetubes were washed with DMF (1.0 mL), and the wash DMF was combined withthe originally transferred material. The solvents were removed, andEtOAc (1 mL) and DI water (1 mL) were added to each tube. Afteragitation and centrifugation, the supernatant was transferred to a new13×100 mm test tube. The aqueous phase was extracted two more times withfresh EtOAc (1 mL). The combined organic phases were back extracted withDI water (1 mL) and aq. NaCl (1 mL). The organic phase was filteredthrough a syringe filter, and the filtrate was evaporated. The residueswere reconstituted in DMSO, and the crude material was subjected to HPLCpurification using acetonitrile/water with 0.05% TFA as the mobile phaseon an Agilent Zorbax Extend C18 column.

Commercially available compound 31 is converted to compound 32 byreacting with amine of the formula R₂—O-A-NH₂, wherein A is optionallysubstituted C₃₋₁₀ cycloalkyl, in a suitable solvent such as, forexample, dimethylacetamide, in the presence of bases such as potassiumcarbonate and diisopropylethyl amine, at elevated temperature rangingfrom 40° C. to 220° C. for a period of time ranging from a few hours toa few days. Compound 32 is converted to compound 33 wherein X is Cl, Bror I by treatment with N-halosuccinamide in a suitable solvent such aschloroform or carbon tetrachloride, at ambient temperature for a periodof time ranging from 30 min to a few hours. Compound 33 is converted tocompound 34 by reacting with an acrylate ester in the presence oftri-o-tolylphosphine, palladium (II) acetate and triethylamine at anelevated temperature. Compound 34 is converted to compound 35 by heatinga solution of compound 34, thiophenol or KOtBu, and organic bases suchas triethylamine and DBU, in a suitable solvent such asdimethylacetamide at an elevated temperature ranging from 40° C. to 220°C. for a period of time ranging from a few hours to a few days. Compound35 is converted to compound 36 by treatment with N-halosuccinamide in asuitable solvent such as DMF at ambient temperature for a period of timeranging from 30 min to a few hours. Compound 36 is then converted tocompound 37 by reacting with boronic acid of the formula R₃—B(OH)₂ or acorresponding boronic ester, in the presence of a base, for example,potassium carbonate, and bis(triphenylphosphine) palladium (II)chloride, in a suitable solvent such as DMF and water solution, at anelevated temperature ranging from 70° C. to 150° C., for a period oftime from several hours to a few days.

Compound of the formula 34 can also be prepared as described in MethodI. Compound 38 is converted to compound 39 by reacting with amine of theformula HO-A-NH₂ in a suitable solvent such as, for example,dimethylacetamide, in the presence of bases such as potassium carbonateand diisopropylethyl amine, at elevated temperature ranging from 40° C.to 220° C. for a period of time ranging from a few hours to a few days.Compound 39 is converted to compound 40 by reacting with R₂X in asuitable solvent such as DMF in the presence of a base such as sodiumhydride at temperature ranging from room temperature to 100° C. Compound40 is converted to compound 41 by treating with hydroxylamine in aqueousethanol at temperature ranging from room temperature to 80° C. Compound41 is converted to compound 34 by reacting with an acrylate ester in thepresence of tri-o-tolylphosphine, palladium (II) acetate andtriethylamine at an elevated temperature. Compound 34 is then convertedto compound of formula 37 following the procedures described in MethodH.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. Examples 1 to 100 provide detailed syntheticsteps for preparing Compounds 101, 104-107, 109, 113-114, 116, 120-121,123, 129-130, 132-133, 147-152, 179, 192, 193, 247-252, 263-264,267-270, 275, 284, and 285 of the present invention. Table 1 showscompounds of the present invention that were prepared using the generalmethods A-I described herein. Table 2 shows the biochemical and cellulardata for the compounds of the present invention. Table 3 shows mousexenograft efficacy data for a representative Compound 152 of the presentinvention. Table 4 shows data on pharmacokinetic and pharmacodynamic(PK-PD) correlation in xenograft models.

It is to be understood that the scope of the present invention is notlimited in any way by the scope of the following examples andpreparations. In the following examples molecules with a single chiralcenter, unless otherwise noted or indicated by the structural formula orchemical name, exist as a racemic mixture. Those molecules with two ormore chiral centers, unless otherwise noted or indicated by thestructural formula or chemical name, exist as a racemic mixture ofdiastereomers. Single enantiomers/diastereomers may be obtained bymethods known to those skilled in the art.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company, and used withoutfurther purification, unless indicated otherwise. ¹H-NMR spectra wererecorded on a Bruker instrument operating either at 300 MHz, or 400 MHzand ¹³C-NMR spectra were recorded operating at 75 MHz. NMR spectra wereobtained as CDCl₃ solutions (reported in ppm), using chloroform as thereference standard (7.25 ppm and 77.00 ppm) or DMSO-D₆ (2.50 ppm and39.51 ppm) or CD₃OD (3.4 ppm and 4.8 ppm and 49.3 ppm), or internaltetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents wereused as needed. When peak multiplicities are reported, the followingabbreviations are used: s (singlet), d (doublet), t (triplet), m(multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hertz (Hz).

Example 12-Amino-8-cyclopentyl-6-(3-hydroxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 147)

To a solution of2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(100 mg, 0.31 mmol), 3-hydroxyphenylboronic acid (50 mg, 1.2 equiv),dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8mL). The solution was degassed with N₂ for 10 min before being cappedand heated in the microwave reactor for 10 min at 120° C. Once complete,the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). TheEtOAc layer was separated, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The crude product was submitted forchromatography purification. The title compound was obtained in (82.1mg, 79% yield).

LRMS: 337 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): 9.37 (1H, s), 7.87 (1H, s), 7.19 (3H, m),7.11 (1H, s), 7.03 (1H, d), 6.74-6.71 (1H, m), 6.04-5.99 (1H, m), 2.55(3H, s), 2.24-2.22 (2H, m), 2.02 (2H, m), 1.77-1.75 (2H, m), 1.60-1.58(2H, m).

Example 22-Amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.80 g, 2.16 mmol) in dioxane (5 mL) was added ammonium hydroxide (30%,2.6 mL). The mixture was then heated at 110° C. in a sealed tube for 30minutes. The solution was concentrated in vacuo and extracted with ethylacetate (3×30 mL). The combined organics were washed with saturatedaqueous sodium chloride, dried (anhydrous sodium sulfate), filtered andconcentrated to dryness to give the title compound as a browncrystalline solid (0.65 g, 93%).

LRMS: 324 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): 8.34 (1H, s), 7.27 (2H, bs), 6.01-5.93 (1H,m), 2.51 (3H, s), 2.16-2.13 (2H, m), 2.00-1.98 (2H, m), 1.75-1.72 (2H,m), 1.57-1.54 (2H, m).

Example 36-Bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Following the procedure described in Example 2, using methylamine (2M inTHF) in place of ammonium hydroxide, the title compound was obtained in90% yield.

LRMS: 338 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): 8.36 (1H, s), 7.82 (1H, bs), 5.98-5.94 (1H,m), 2.86 (3H, s), 2.51 (3H, s), 2.28 (2H, m), 1.99-1.97 (2H, m),1.75-1.72 (2H, m), 1.62 (2H, m).

Example 46-Bromo-8-cyclopentyl-4-methyl-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Following the procedure described in Example 2, using ethylamine (2M inTHF) in place of ammonium hydroxide, the title compound was obtained in93% yield.

LRMS: 352 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): 8.35 (1H, s), 7.90 (1H, bs), 6.01-5.93 (1H,m), 3.34 (2H, m), 2.51 (3H, s), 2.27 (2H, m), 1.96 (2H, m), 1.75 (2H,m), 1.62 (2H, m), 1.15 (3H, m).

Example 5 Preparation of2-amino-8-cyclopentyl-6-(1H-pyrazol-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 101)

To a solution of2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(100 mg, 0.31 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate 110 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II)(6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was addedpotassium carbonate (3 M, 0.8 mL). The solution was degassed with N₂ for10 min before being capped and heated in the microwave reactor for 10min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10mL) and EtOAc (50 mL). The EtOAc layer was washed with 3N HCl, driedover MgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was submitted for chromatography purification. the titlecompound was obtained in (62.5 mg, 65% yield).

LRMS: 311 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): 8.26 (2H, bs), 8.13 (1H, s), 7.09 (2H, bs),6.04-5.99 (1H, m), 2.59 (3H, s), 2.27-2.23 (2H, bm), 2.04 (2H, bm),1.77-1.74 (2H, bm), 1.62 (2H, bm).

Example 62-Methylamino-6-carbonitrile-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 133)

A solution of6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one(150 mg, 0.15 mmol) and tetraethylammonium cyanide 946 mg, 0.30 mmol);DABCO (33 mg, 0.30 mmol) in acetonitrile (2 mL) was stirred at 22° C.for 3 days. The reaction appears completed by LCMS and the mixture wasevaporated and sent for chromatography. (70.6 mg, 61% yield).

LRMS: 284 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.68 (1H, s), 8.31 (1H, m), 5.90-5.85 (1H, m),2.91 (3H, m), 2.51 (3H, s), 2.28 (2H, bm), 1.96 (2H, bm), 1.77 (2H, bm),1.62 (2H, bm).

Example 78-Cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide(Compound 123)

A solution of2-methylamino-6-carbonitrile-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(90 mg, 3.20 mmol) in 3M HCl (10 mL) was stirred at 110° C. for 24 h.The reaction appears completed by LCMS and the mixture was evaporatedand sent for chromatography. (32.2 mg, 45% yield).

LRMS: 302 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.80 (1H, bs), 8.68 (1H, s), 8.13 (1H, m), 7.62(1H, bs), 5.98-5.96 (1H, m), 2.91 (3H, m), 2.51 (3H, s), 2.33 (2H, bm),1.99 (2H, bm), 1.78 (2H, bm), 1.65 (2H, bm).

Example 8(E)-8-cyclopentyl-6-(2-hydroxyvinyl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 120)

6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(336 mg, 1.0 mmole), 1-(vinyloxy)butane (501 mg, 5.0 mmole),N-cyclohexyl-N-methylcyclohexanamine (254 mg, 1.3 mmole),tri-tert-butylphosphonium tetrafluoroborate (8.70 mg, 0.03 mmole),lithium chloride (127 mg, 3.0 mmole),tris(dibenzylideneacetone)dipalladium(0)) (27.5 mg, 0.03 mmole) and1,4-dioxane (10 ml) were added to a reaction vial equipped with a stirbar. The reaction vial was flushed with nitrogen, capped, and heated at75° C. for 75 min. LCMS data indicated that both the intermediate vinylether and the product were obtained (4:6). The reaction mixture wascooled to ambient temperature, filtered through Celite™ and washed withdioxane (10 ml). The filtrate and washing were combined, andpara-toluene sulfonic acid monohydrate (761 mg, 4.0 mmole) was added.The reaction was stirred at ambient temperature for 1 h. At this pointLCMS data indicated that all of the intermediate vinyl ether hydrolyzedto the desired product. The solvent was removed under reduced pressureto a residue, and ethyl acetate (120 ml) was added, and washed withaqueous potassium carbonate solution (5 wt/v %), water, and brine. Theorganic layer was dried over sodium sulfate, and the solvent was removedunder reduced pressure to a yellow solid residue, which was crystallizedfrom boiling heptane. Upon cooling to ambient temperature, yellowcrystals formed and collected by filtration to give the title compound(190 mg, 62% yield) after two steps.

LCMS: 301 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 8.49 (s, 1H) 5.79-6.19 (m, 1H) 5.23-5.76 (m, 1H)3.10 (d, J=4.78 Hz, 3H) 2.72 (s, 3H) 2.60 (s, 3H) 2.34-2.54 (m, 2H)1.98-2.15 (m, 2H) 1.80-1.94 (m, 2H) 1.65-1.78 (m, 2H).

¹H NMR (DMSO-d6, 400 MHz) 8.35 (s, 1H) 7.81-8.21 (m, 1H) 5.75-6.05 (m,1H) 2.90 (t, J=5.41 Hz, 3H) 2.60 (s, 1H) 2.53-2.57 (m, 5H) 2.20-2.42 (m,2H) 1.91-2.11 (m, 2H) 1.70-1.85 (m, 2H) 1.52-1.69 (m, 2H).

Example 9 (E)-Ethyl3-(8-cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acrylate

6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(375 mg, 1.1 mmole), ethyl acrylate (442 mg, 4.42 mmole),N-cyclohexyl-N-methylcyclohexanamine (280 mg, 1.43 mmole),tri-tert-butylphosphonium tetrafluoroborate (9.61 mg, 0.03 mmole),lithium chloride (42.4 mg, 3.3 mmole),tris(dibenzylideneacetone)dipalladium(0)) (30.3 mg, 0.03 mmole) and1,4-dioxane (10 ml) were added to a reaction vial equipped with a stirbar. The reaction vial was flushed with nitrogen, capped, and heated at75° C. for 75 min. The reaction mixture was cooled to ambienttemperature, filtered through Celite™, and washed with ethyl acetate.The filtrate and washing were combined, and the volatiles were removedunder reduced pressure to a yellow solid residue. This solid residue wascrystallized from boiling heptane:ethyl acetate (50 ml: 50 ml). Uponcooling to ambient temperature, needle-liked yellow crystals formed andcollected by filtration to give the title compound as a beta-transisomer (356 mg, 90% yield).

LCMS: 357 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 7.88 (s, 1H) 7.71 (d, J=15.86 Hz, 1H) 6.96 (d,J=15.86 Hz, 1H) 6.03 (s, 1H) 5.46 (s, 1H) 4.25 (q, J=7.22 Hz, 2H) 3.09(d, J=5.04 Hz, 3H) 2.58 (s, 3H) 2.42 (s, 2H) 1.91-2.19 (m, 3H) 1.86 (s,2H) 1.28-1.37 (m, 3H).

Example 10 Ethyl3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoate(Compound 132)

(E)-ethyl3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acrylate(525 mg, 1.4 mmole) obtained in an analogous manner to Example 9 wasdissolved in ethanol (150 ml) in a 500 ml-Parr™ reaction bottle, and thesolution was degassed with nitrogen for 5 min. Pd/C (450.0 mg) (Aldrich330108-50G, batch 08331KC, Palladium, 10 wt % dry basis on activatedcarbon, wet, Degussa type E101 NE/W, water ca. 50%) was added. Thereaction was hydrogenated at 50 psi hydrogen at ambient temperature for18 h. The catalyst was filtered and washed with ethanol (20 ml). Thefiltrate and washing were combined and the volatiles were removed underreduced pressure to a solid residue. The residue was crystallized fromboiling heptane (30 ml). Upon cooling to ambient temperature, whiteneedle-liked crystals formed, and collected by filtration to give thetitle compound (338 mg, 64% yield).

LCMS: 373 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 7.55 (s, 1H) 5.83-6.12 (m, J=17.88, 8.81, 8.56Hz, 1H) 5.21 (s, 1H) 4.12 (q, J=7.13 Hz, 2H) 3.38-3.63 (m, 2H) 2.87 (t,J=7.30 Hz, 2H) 2.67 (t, J=7.30 Hz, 2H) 2.53 (s, 3H) 2.31-2.46 (m, 2H)1.99-2.10 (m, 2H) 1.77-1.91 (m, 2H) 1.63-1.74 (m, 2H) 1.19-1.31 (m, 6H).

Example 113-(8-Cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoicacid (Compound 130)

Ethyl3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoate(167 mg, 0.45 mmole) was dissolved in THF (5 ml) in a reaction vialequipped with a stir bar. Lithium hydroxide (35 mg, 1.46 mmole) wasdissolved in water (5 ml) and then added to the reaction vial. Thereaction mixture was stirred at ambient temperature for 3 h. Thevolatiles were removed under reduced pressure to a white solid residue.Aqueous hydrochloric acid (3.26 mmole, 3.26 ml of 1.0 M solution) wasadded. The white solid was collected by filtration as the title compound(125 mg, 81% yield).

LCMS: 345 (M+H)⁺.

¹H NMR (D₂O, 400 MHz) 7.54 (s, 1H) 5.56-5.81 (m, 1H) 3.22 (q, J=7.22 Hz,2H) 2.60 (t, J=7.55 Hz, 2H) 2.31-2.38 (m, 5H) 1.91-2.05 (m, 2H)1.77-1.90 (m, 2H) 1.58-1.71 (m, 2H) 1.46-1.58 (m, 2H) 1.06 (t, J=7.30Hz, 3H).

Example 123-(8-Cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide(Compound 121)

3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoicacid (94 mg, 0.27 mmole), dimethylamine (1.09 mmole, 0.55 ml of 2.0 Msolution in THF), triethylamine (27.6 mg, 0.27 mmole),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU, 104 mg, 0.27 mmole) and DMF (3.0 ml) wereadded to a reaction vial equipped with a stir bar. The reaction mixturewas heated at 50° C. for 26 h. The reaction was quenched with water (2ml), and the volatiles were removed under reduced pressure to a residue.Ethyl acetate (70 ml) and water (30 ml) were added and shaken well. Theorganic layer was separated, washed with water (2×30 ml), brine (30 ml),and dried over sodium sulfate. The solvent was removed under reducedpressure to a residue, which was purified using silica (100% petroleumether to 100% ethyl acetate). The fractions were combined, and thevolatiles were removed to a colorless oil as the title compound (55 mg,54% yield).

LCMS: 372 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 7.66 (s, 1H) 5.85-6.07 (m, 1H) 3.38-3.60 (m, 2H)3.03 (s, 3H) 2.94 (s, 3H) 2.88 (t, J=7.30 Hz, 2H) 2.68 (t, J=7.43 Hz,2H) 2.54 (s, 3H) 2.34-2.48 (m, 2H) 1.97-2.14 (m, 2H) 1.78-1.91 (m, 2H)1.62-1.75 (m, 3H) 1.27 (t, J=7.18 Hz, 3H).

Example 138-Cyclopentyl-2-(ethylamino)-6-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 129)

Ethyl-3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoate (60 mg, 0.16 mmole) was dissolved in ethanol (5 ml) andmethanol (2 ml). Sodium borohydride (18 mg, 0.48 mmole) was slowly addedto the reaction solution. The reaction progress was monitored by LCMS.More sodium borohydride was added in portions to push the reaction tocompletion after 20 h at ambient temperature. The reaction was quenchedwith water, and the solvents were removed under reduced pressure todryness. Water (15 ml) was added, and the product was extracted withethyl acetate (3×30 ml). The organic layer was dried over sodiumsulfate, and the solvent was removed under reduced pressure to aresidue, which was purified by HPLC. The TFA salt form of product wasfree-based to give the title compound (34 mg, 61% yield).

LCMS: 331 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 7.53 (s, 1H) 5.85-6.12 (m, 1H) 3.57-3.65 (m, 2H)3.51-3.57 (m, 2H) 2.96 (s, 1H) 2.71 (t, J=7.05 Hz, 2H) 2.58 (s, 3H) 2.35(s, 2H) 1.99-2.12 (m, 2H) 1.79-1.91 (m, 4H) 1.61-1.77 (m, 3H) 1.28 (t,J=7.18 Hz, 3H).

Example 148-Cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-6-(3-hydroxyphenyl)-4-methylpyrido[2,3-d]-pyrimidin-7(8H)-one(Compound 114)

To a solution of6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(52.5 mg, 0.133 mmol), 3-hydroxyphenylboronic acid (20.5 mg, 0.149mmol), potassium carbonate (3 M, 0.06 mL) in DMF (1.2 mL) was addeddichlorobis(triphenylphosphine)palladium(II) (5 mg, 0.007 mmol). Themixture was degassed with N₂, sealed and heated for 30 min at 110° C.The mixture was poured into brine and extracted with EtOAc. The EtOAclayer was dried (anhydrous sodium sulfate), filtered, and concentratedunder reduced pressure. The crude product was purified by chromatographyto give the title compound (12 mg, 22%).

LRMS: 409 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 7.73 (1H, s), 7.28-7.33 (1H, m), 7.09-7.20 (2H,m), 6.79-6.89 (1H, m), 5.90-6.10 (1H, m), 5.13-5.88 (1H, m), 3.54 (2H,d, J=6.32 Hz), 2.58 (3H, s), 2.25-2.49 (2H, m), 1.96-2.18 (2H, m),1.79-1.95 (2H, m), 1.63-1.77 (4H, m), 1.31 (6H, s).

Example 156-Bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(600 mg, 1.62 mmol) and 1-amino-2-methylpropan-2-ol (294 mg, 2.34 mmol)in dioxane (6 mL) was added triethylamine (1.2 mL, 8.6 mmol). Themixture was then heated at 110° C. in a sealed tube for 1 h. Thesolution was poured into brine and extracted with ethyl acetate. Theorganic was dried (anhydrous sodium sulfate), filtered and concentratedto dryness. The crude product was purified by silica gel flashchromatography to give the title compound as a solid (565 mg, 88%).

LRMS: 395, 397 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.07 (1H, s), 5.91-6.13 (1H, m), 5.46-5.90 (1H,m), 3.52 (2H, d, J=6.32 Hz), 2.54 (3H, s), 2.17-2.43 (2H, m), 1.95-2.16(2H, m), 1.76-1.95 (2H, m), 1.56-1.74 (3H, m), 1.30 (6H, s).

Example 168-Cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 116)

To a solution of6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(50 mg, 0.126 mmol), 6-methoxypyridin-3-ylboronic acid (21 mg, 0.137mmol), potassium carbonate (3 M, 0.06 mL) in DMF (1.2 mL) was addeddichlorobis(triphenylphosphine)palladium(II) (4.5 mg, 0.0064 mmol). Themixture was degassed with N₂, sealed and heated for 30 min at 110° C.The solvent was removed under reduced pressure. The crude mixture waspurified by chromatography to give the title compound (23.6 mg, 44%).

LRMS: 424 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.31 (1H, d, J=2.27 Hz), 7.97 (1H, dd, J=8.59,2.53 Hz), 7.72 (1H, s), 6.81 (1H, d, J=8.59 Hz), 5.88-6.12 (1H, m),5.28-5.86 (1H, m), 3.97 (3H, s), 3.55 (2H, d, J=6.32 Hz), 2.59 (3H, s),2.26-2.47 (2H, m), 1.98-2.17 (2H, m), 1.79-1.98 (2H, m), 1.65-1.77 (3H,m), 1.32 (6H, s).

Example 178-Cyclopentyl-4-methyl-2-(methylamino)-6-(pyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 107)

Following the procedure described in Preparation of Example 14, using6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,pyrimidin-5-ylboronic acid in place of 3-hydroxyphenylboronic acid, thetitle compound was obtained in 10% yield.

LRMS: 337 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 9.19 (1H, s), 9.03 (1H, s), 7.80 (1H, s),5.69-6.29 (1H, m), 3.11 (3H, d, J=5.05 Hz), 2.65 (3H, s), 2.27-2.54 (2H,m), 1.97-2.25 (4H, m), 1.82-1.97 (2H, m), 1.51-1.80 (2H, m).

Example 188-Isopropyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 113)

Following the procedure described in Preparation of Example 14, using6-bromo-8-isopropyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,the title compound was obtained in 11% yield.

LRMS: 340 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 8.31 (1H, d, J=2.02 Hz), 7.99 (1H, dd, J=8.72,2.40 Hz), 7.71 (1H, s), 6.80 (1H, d, J=8.59 Hz), 5.72-6.03 (1H, m), 3.97(3H, s), 3.09 (3H, d, J=5.05 Hz), 2.58 (3H, s), 1.65 (6H, d, J=6.82 Hz).

Example 196-Bromo-8-isopropyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

To a stirred solution of6-bromo-8-isopropyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(175 mg, 0.508 mmol) in 1,4-dioxane (2.5 mL) was added methyl amine(0.80 mL, 2.0 M in THF, 1.6 mmol). The mixture was sealed and heated at110° C. microwave for 15 min. The solvent was evaporated and the crudeproduct was washed with EtOAc/Hexane to give the title compound (158 mg,76%).

LRMS: 311, 313 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.06 (1H, s), 5.55-6.19 (1H, m), 5.19-5.46 (1H,m), 3.07 (3H, d, J=5.05 Hz), 2.52 (3H, s), 1.62 (6H, d, J=6.32 Hz).

Example 206-Bromo-8-isopropyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a stirred and cooled (−20° C.) solution of6-bromo-8-isopropyl-4-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one(380 mg, 1.16 mmol) in CH₂Cl₂ (25 mL) was added MCPBA (340 mg, 77%, 1.52mmol). After stirring for 30 min (−20° C. to 0° C.), the mixture wasquenched with saturated aqueous NaHCO₃, extracted with EtOAc, dried andevaporated. The crude product was washed with EtOAc/Hexane to give thetitle compound (190 mg, 48%).

LRMS: 344, 346 (M+H)⁺.

¹H NMR (DMSO-d6, 400 MHz): 8.78 (1H, s), 5.60-5.97 (1H, m), 2.92 (3H,s), 2.79 (3H, s), 1.56 (6H, d, J=6.82 Hz).

Example 216-Bromo-8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a suspension of NaH (120 mg, 5.00 mmol) in DMF (15 mL) was added6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (572 mg,2 mmol). The mixture was heated to 46° C. The solution was cooled downslightly and 2-iodopropane (0.30 mL, 3.0 mmol) was added. The mixturewas heated at 46° C. for 30 min and then cooled to room temperature andpartitioned between water and ethyl acetate. The organic phase was dried(MgSO₄) and concentrated. The crude product was purified by silica gelflash chromatography, using EtOAc/Hexane, to give the title compound(390 mg, 59%).

LRMS: 328, 330 (M+H)⁺.

¹H NMR (DMSO-d6, 400 MHz): 8.60 (1H, s), 5.45-5.99 (1H, m), 2.64 (3H,s), 2.58 (3H, s), 1.54 (6H, d, J=6.82 Hz).

Example 226-(5-(Aminomethyl)-2-fluorophenyl)-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 104)

To a solution of8-cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-ylboronicacid (30 mg, 0.099 mmol), 3-bromo-4-fluorobenzylamine hydrochloride(28.7 mg, 0.119 mmol), potassium carbonate (3 M, 0.10 mL) in DME (0.5mL) and EtOH (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The mixture was degassed with N₂,sealed and heated for 1 h at 100° C. in microwave. The mixture wasremoved under reduced pressure. The crude product was purified bychromatography to give the title compound (16.4 mg, 43.3%).

LRMS: 382 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 7.73 (1H, s), 7.46 (1H, d, J=6.06 Hz),7.29-7.40 (1H, m), 7.07 (1H, t, J=8.84 Hz), 6.14-6.73 (1H, m), 5.78-6.12(1H, m), 3.84-4.11 (2H, m), 3.08 (3H, d, J=4.80 Hz), 2.48-2.67 (4H, m),2.32 (3H, d, J=6.57 Hz), 1.91-2.06 (2H, m), 1.75-1.91 (2H, m), 1.51-1.72(2H, m).

Example 238-Cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-ylboronicacid

To a stirred and cooled (−78° C.) solution of6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one(1.00 g, 2.94 mmol) and trimethylborate (1.40 mL, 12.6 mmol) in THF (60mL) was added BuLi (9.5 mL, 1.6 M, 15.2 mmol). After stirring for 20min, the mixture was quenched with small amount of 2 N HCl and water,extracted with EtOAc (3 times), dried and evaporated. The crude mixturewas purified by silica gel chromatography to give the title compound(157.2 mg, 18%).

LRMS: 303 (M+H)⁺.

¹H NMR (DMSO-d6, 400 MHz): 8.58 (1H, s), 8.57 (1H, s), 8.36 (1H, s),7.58-8.03 (1H, m), 5.64-6.14 (1H, m), 2.79-2.98 (3H, m), 2.52-2.62 (3H,m), 2.12-2.41 (2H, m), 1.87-2.12 (2H, m), 1.44-1.86 (4H, m).

Example 246-(6-Methoxypyridin-3-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 153)

To a solution of6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(147 mg, 0.445 mmol) in 1,4-dioxane (2.5 mL) was added methylamine (1.1mL, 2.0 M in THF, 2.2 mmol). The mixture was sealed and heated at 110°C. microwave for 10 min. The mixture was concentrated under reducedpressure to give a solid. The crude solid was washed with water andEtOAc, recrystallized from DMSO/EtOAc to give the title compound (80 mg,61%).

LRMS: 298 (M+H)⁺.

¹H NMR (DMSO-d6, 400 MHz): 11.68-12.05 (1H, m), 8.50 (1H, d, J=1.77 Hz),8.05 (1H, dd, J=8.59, 2.53 Hz), 8.02 (1H, s), 7.23-7.71 (1H, m), 6.86(1H, d, J=8.59 Hz), 3.89 (3H, s), 2.86 (3H, d, J=4.29 Hz), 2.54 (3H, s).

Example 256-(6-Methoxypyridin-3-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Following the procedure described in Example 20, using6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-bromo-8-isopropyl-4-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one,the title compound was used as crude to the next step.

LRMS: 331 (M+H)⁺.

Example 266-(6-Methoxypyridin-3-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg,0.17 mmol), 6-methoxypyridin-3-ylboronic acid (40.1 mg, 1.1 equiv),dichlorobis(triphenylphosphine) palladium(II) (6.13 mg, 0.008 mmol), DMF(2 mL) in a 5 mL microwave vial was added potassium carbonate (3 M, 1.1equiv). The solution was degassed with N₂ for 10 min before being cappedand heated in the microwave reactor for 1 h. at 100° C. The reaction waspoured into 20 ml brine and the precipitate was collected by filtration.It was further purified by chromatography (80% thylacetate/hexane). Thetitle compound was obtained as a solid (30 mg, 55% yield).

LRMS: 315.0 (ES+)

¹H NMR (DMSO-d6, 400 MHz): 12.54 (1H, s), 8.56 (1H, d, J=2.27 Hz), 8.20(1H, s), 8.10 (1H, dd, J=8.72, 2.40 Hz), 6.90 (1H, d, J=8.59 Hz), 3.90(3H, s), 2.70 (3H, s), 2.57 (3H, s).

Example 278-Cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 109)

Following the procedure described in Example 22, using8-cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one,the title compound was obtained in 35% yield.

LRMS: 352 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.31 (1H, d, J=2.02 Hz), 7.98 (1H, dd, J=8.72,2.40 Hz), 7.71 (1H, s), 6.80 (1H, d, J=8.59 Hz), 5.76-6.10 (1H, m), 5.41(1H, s), 3.97 (1H, s), 3.18-3.44 (2H, m), 3.12 (3H, d, J=5.05 Hz), 2.56(3H, s), 2.24-2.46 (2H, m), 2.01 (1H, q, J=10.36 Hz), 1.78-1.93 (1H, m).

Example 288-Cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Following the procedure described in Example 24, using8-cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-bromo-8-isopropyl-4-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one,the title compound was used as crude to the next step.

LRMS: 385 (M+H)⁺.

Example 298-Cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

Following the procedure described in Example 12, using6-bromo-8-cyclobutyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onein place of6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one,the title compound was obtained in 78% yield.

LRMS: 369 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.35 (1H, d, J=2.53 Hz), 7.99 (1H, dd, J=8.59,2.53 Hz), 7.79 (1H, s), 6.82 (1H, d, J=8.59 Hz), 5.80-6.13 (1H, m), 3.98(3H, s), 3.07-3.41 (2H, m), 2.69 (3H, s), 2.68 (3H, s), 2.29-2.52 (2H,m), 1.78-2.11 (2H, m).

Example 306-Bromo-8-cyclobutyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 100);6-bromo-7-cyclobutoxy-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine(Compound 99)

To a solution of6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg,1.75 mmol) and cyclobutanol (164 mg, 2.27 mmol) in THF (40 mL) was addedtriphenylphosphine (917 mg, 3.49 mmol) and DEAD (852 mg, 4.89 mmol).After 2 h, the mixture was poured into brine, extracted with ethylacetate, dried (anhydrous Na₂SO₄) and evaporated. The mixture waspurified by chromatography to give Compound 100 (97 mg, 16%) andCompound 99 (180 mg, 30%).

LRMS: 340, 342 (M+H)⁺.

Compound 100:

¹H NMR (CDCl₃, 400 MHz): 8.18 (1H, s), 5.78-6.12 (1H, m), 3.03-3.34 (2H,m), 2.66 (3H, s), 2.65 (3H, s), 2.25-2.48 (2H, m), 1.95-2.18 (1H, m),1.71-1.95 (1H, m).

Compound 99:

¹H NMR (CDCl₃, 400 MHz): 8.38 (1H, s), 5.45-5.74 (1H, m), 2.77 (3H, s),2.69 (3H, s), 2.53-2.66 (2H, m), 2.17-2.37 (2H, m), 1.81-1.98 (1H, m),1.65-1.81 (1H, m).

Example 312-Amino-8-cyclopentyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 106)

To the solution of8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(80 mg, 0.17 mmol) in 5 ml 1,4-dioxane was babbled through ammonium gasfor 10 minutes. The reaction tube was sealed and heated to 100° C. for30 minutes. The reaction mixture was poured into brine and theprecipitate was collected via filtration. The solid was thenre-dissolved in 5 ml methanol and a few drop of concentrated HCl wasadded and the mixture was heated to 50° C. for 5 hours. The reactionmixture was cooled down to room temperature. Solvent was removed via rotvap and the residue was triturated with ethylacetate/hexane to give thetitle compound (33 mg, 54% yield).

LCMS: 355.20 (ES+)

¹H NMR (DMSO-d₆, 400 MHz): 8.44 (s, 1H), 8.17 (d, J=4.29 Hz, 2H), 7.11(s, 2H), 6.21-6.02 (m, 1H), 4.96 (s, 1H), 4.23 (t, J=5.56 Hz, 2H), 3.81(t, J=5.18 Hz, 2H), 2.64 (s, 3H), 2.39-2.22 (m, 2H), 2.19-2.06 (m, 2H),1.88-1.74 (m, 2H), 1.74-1.56 (m, 2H).

Example 328-Cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

m-CPBA (209 mg, 2.0 equiv.) was added into the solution of8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(200 mg, 0.46 mmol) in 10 ml methylene chloride at room temperature. Itwas stirred at room temperature for 2 hour. The solvent was removed viarot vap and the residue was purified by chromatography (30 to 80%ethylacetate/hexane) to give the title compound (166 mg, 77% yield).

LCMS: 462.1 (ES+)

¹H NMR (CDCl₃, 400 MHz): 8.51 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H),6.13-6.00 (m, 1H), 4.61 (s, 2H), 4.40 (t, J=5.31 Hz, 2H), 3.97 (t,J=5.31 Hz, 2H), 3.39 (s, 3H), 3.30 (s, 3H), 2.91 (s, 3H), 2.40-2.28 (m,2H), 2.24-2.12 (m, 2H), 2.03-1.91 (m, 2H), 1.81-1.70 (m, 2H).

Example 338-Cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-bromo-8-cyclopentyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(200 mg, 0.56 mmol),1-(2-(methoxymethoxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(239 mg, 1.5 equiv), palladium (0) tetrakis(triphenylphosphine) (6.13mg, 0.05 equiv.), DMF (2 mL) in a 5 mL microwave vial was addedpotassium carbonate (3 M, 3.0 equiv). The solution was degassed with N₂for 10 min before being capped and heated in the microwave reactor for30 min. at 100° C. The reaction was poured into 20 ml brine and theprecipitate was collected by filtration. The title compound was obtainedas a solid (208 mg, 86% yield). It was used for next step withoutfurther purification.

LRMS: 430.0 (ES+).

Example 348-Cyclopentyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 105)

8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(80 mg, 0.17 mmol) was dissolved into 3 ml methylamine in THF (1.0 M).The reaction mixture was then heated to 100° C. in microwave for 30minutes. The solvent was removed via rot vap and the residue wasre-dissolved in 5 ml methanol. A few drop of concentrated HCl was addedthe mixture was heated to 50° C. for 5 hours. The reaction mixture wascooled down to room temperature. Solvent was removed via rot vap and theresidue was triturated with ethylacetate/hexane to give the titlecompound (45 mg, 70% yield).

LRMS: 369.20 (ES+)

¹H NMR (CDCl₃, 400 MHz): 8.33 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H),6.11-5.98 (m, 1H), 4.34-4.24 (m, 2H), 4.08-4.00 (m, 2H), 3.09 (d, J=5.05Hz, 3H), 2.65 (s, 3H) 2.50-2.37 (m, 2H) 2.15-2.04 (m, 2H) 1.94-1.83 (m,2H) 1.79-1.64 (m, 2H).

Example 358-Cyclopentyl-6-(3-(hydroxymethyl)phenyl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 148)

6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one(5.00 g, 14.83 mmol), 3-(hydroxymethyl)phenylboronic acid (3.38 g, 22.24mmol) and Pd(PPh₃)₄ (0.685 g, 0.593 mmol) were suspended in Toluene (20mL), MeOH (10 mL) and sat. NaHCO₃ (10 mL) and then heated to 100° C.overnight. The reaction was deemed complete by MS and TLC. The organiclayer was injected directly onto a column, eluting with CH₂Cl₂ then 4%MeOH in CH₂Cl₂. The fractions containing the desired material, as deemedby MS, were combined and evaporated in vacuo to give a greenish beigesolid. This was triturated with MeCN and filtered to give crop one, 4.7g. A second crop was obtained of 0.25 g. A third crop was obtained of0.10 g. The three crops were deemed to be of sufficient purity based onNMR's and were combined and washed again with MeCN to give a solid (4.39g, 81.24%).

Elemental Analysis: Calcd for C₂₁H₂₄N₄O₂, C, 69.21/69.00; H, 6.64/6.65;N, 15.37/15.16.

LRMS (M+H)⁺: 365.1

¹H NMR (CDCl₃, 400 MHz): 7.73 (1H, s) 7.61 (1H, s), 7.53 (1H, d, J=7.57Hz), 7.40 (1H, t, J=7.69 Hz), 7.34 (1H, d, J=7.57 Hz), 6.04 (1H, m),5.27 (1H, s), 4.74 (2H, d, J=6.11 Hz), 3.06 (3H, d, J=5.13 Hz), 2.56(3H, s), 2.40 (2H, m), 2.05 (2H, m), 1.66 (2H, m).

Example 366-Bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-Bromo-8-cyclopentyl-2-methanesulfinyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(8.00 g, 22.04 mmol) was dissolved in 100 mL of CH₂Cl₂, then NH₂Me wasbubbled in for 3 minutes. The reaction was diluted with CH₂Cl₂ andwashed with water. The organic layer was dried over Na₂SO₄ and thesolvent evaporated in vacuo to give an off white solid. The material wasdiluted with CH₂Cl₂ and purified by silica gel chromatography to give anoff white solid (7.33 g, 98.42%).

LRMS: 337.1, 339.1 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): 8.06 (1H, s), 6.04 (1H, s), 5.31 (1H, br s),3.04 (3H, d, J=4.88 Hz), 2.51 (3H, s), 2.29-2.36 (2H, m), 2.03-2.13 (2H,m), 1.80-1.89 (2H, m), 1.61-1.68 (2H, m).

Example 378-(4-Methoxybenzyl)-6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a mixture of sodium hydride (60% dispersion in mineral oil) (90 mg,1.5 equiv.) and anhydrous DMF (5 mL) was added6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (429 mg,1.5 mmol) and the mixture stirred for 30 minutes at 50° C. Solution wasthen cooled a little and p-methoxybenzylchloride (281 mg, 1.2 equiv) in1 mL DMF was then added dropwise. Heated to 50° C. for 3 hours and thenstirred at rt overnight. Cooled to rt, partitioned between water andAcOEt, water further washed with AcOEt, pooled organic extracts washedwith saturated sodium bicarbonate, brine and dried over MgSO4.Filtration and solvent removal afforded crude material which was usedwithout further purification. Yield 675 mg.

LRMS (APCI) 406.3/408.3 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 8.19 (s, 1H), 7.45 (d, 2H), 6.79 (d, J=8.72 Hz,2H), 5.62 (s, 2H), 3.75 (s, 3H), 2.64 (s, 3H), 2.63 (s, 3H).

Example 388-(4-Methoxybenzyl)-4-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

Ref. JMC 2004, 47 (16), p. 4097

To a mixture of bromoolefin (203 mg, 0.5 mmol) in toluene (5 mL) andethanol (5 mL) was added saturated sodium bicarbonate (5 mL), palladiumtetrakis(triphenylphosphine) (29 mg, 5 mol. %), followed byphenylboronic acid (73 mg, 1.2 equiv.). Mixture was heated to 100° C.for 3 hours. Cooled to room temperature, diluted with EA and water,phases separated, aqueous phase washed 2× with 10 mL of EA, combinedorganic phases washed with brine and dried over MgSO₄. Filtered andstripped to give light brown solid (166 mg, 82%). Used withoutpurification.

¹H NMR (CDCl₃, 400 MHz) 7.87 (s, 1H), 7.65 (d, J=7.89 Hz, 2H), 7.38-7.48(m, 5H), 7.11-7.20 (m, 2H), 2.70 (s, 3H), 2.60 (s, 3H), 2.35 (s, 3H).

Example 398-(4-Methoxybenzyl)-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of methyl sulfide (150 mg, 0.372 mmol), m-chloroperbenzoicacid (129 mg, 2 equiv.) in dichloromethane (5 mL) was stirred at rt for4 hours. Solvent was then removed and crude material (232 mg) used fornext step without purification.

Example 408-(4-Methoxybenzyl)-2-amino-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 149)

The crude sulfone compound (220 mg) was dissolved in freshly preparedsaturated ammonia/THF solution and the mixture heated to refluxovernight. Stripped, partitioned between EA and aqueous saturated sodiumbicarbonate, organic portion washed with brine, dried over MgSO₄,filtered and stripped. Purified on Biotage flash column using 1:2hexane/EA. Yellow foam, 55 mg (76%).

LRMS (APCI): 373.4 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz) 7.77 (s, 1H), 7.62 (d, J=7.06 Hz, 2H), 7.51 (d,J=8.72 Hz, 2H), 7.32-7.43 (m, 3H), 6.79 (d, J=8.72 Hz, 2H), 5.55 (s,2H), 5.31 (s, 2H), 3.74 (s, 3H), 2.59 (s, 3H)

Example 418-(4-Chlorobenzyl)-6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To the solution of NaH (90 mg, 2.25 mmol, 1.5 equiv.) in DMF (5 mL) wasat rt added lactam compound (429 mg, 1.5 mmol) and the mixture heated to50° C. for 30 minutes. Cooled to rt, added p-chlorobenzyl bromide (370mg, 1.8 mmol, 1.2 equiv.) as a solution in DMF (1 mL). Heated to 50° C.for 3 hours. Cooled, diluted with water, extracted 3× with. Organicportions combined and washed with brine and dried over MgSO4, filteredand stripped. Orange-brown solid (605 mg, 98% (crude). Used withoutfurther purification.

LRMS (APCI) 410.3/412.3 (M+H)⁺

¹H NMR (CDCl₃) 8.22 (s, 1H), 7.40 (d, J=8.72 Hz, 2H), 7.22-7.31 (m, 2H),5.63 (s, 2H), 2.65 (s, 3H), 2.58 (s, 3H).

Example 428-(4-Chlorobenzyl)-4-methyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

To the solution of bromo compound (205 mg, 0.5 mmol) in toluene/EtOH (5and 5 mL) was added saturated aqueous sodium bicarbonate (3 mL),palladium tetrakis(triphenylphosphine (29 mg, 5 mol %) and phenylboronicacid (73, 0.6 mmol, 1.2 equiv.). Heated to 100° C. for 2 hours and thenallowed to stand at rt for 72 hours. Diluted with EA and water, phasesseparated, organic phase washed with brine and dried over MgSO4.Filtered and stripped to give light yellow solid, 162 mg (80%). Crudematerial used without further purification.

LRMS (M+H)⁺: 408.5

Example 438-(4-Chlorobenzyl)-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

To the solution of methylsulfide (160 mg, 0.39 mmol) in dichloromethane(5 mL) was added m-chloroperbenzoic acid (203 mg, 3 equiv.) in severalsmall portions and the resulting reaction allowed to stir overnight. Thereaction mixture was then washed with saturated aqueous sodiumbicarbonate (2×), brine and dried over MgSO4. Filtration andconcentration gave material as white glassy solid (185 mg) which wasused immediately without purification. Product is likely a mixture ofsulfoxide and sulfone (LC MS).

LRMS (APCI) (M+H)⁺: 440.5.

Example 448-(4-Chlorobenzyl)-2-amino-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 150)

The crude material from previous experiment (150 mg, 0.35 mmol) wasdissolved in a freshly prepared ammonia/THF solution and heated toreflux. After 3 hours, the solvent removed under reduced pressure, theproduct isolated on SCX cartridge and purified on Biotage flash columnusing EA/hexane 1:1. Light yellow foam (90 mg, 70%).

LRMS (APCI) 377.4 (M+H)⁺,

¹H NMR (400 MHz, CDCl₃): 7.80 (s, 1H), 7.62 (d, 2H), 7.33-7.46 (m, 5H),7.22 (d, 2H), 5.57 (s, 2H), 5.27 (bs, 2H, NH2), 2.60 (s, 3H).

Example 458-(4-Chlorobenzyl)-4-methyl-2-(methylthio)-6-(pyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To the solution of bromo compound (150 mg, 0.366 mmol), prepared asdescribed in Example 41, in toluene/EtOH (2 and 2 mL) was addedsaturated aqueous sodium bicarbonate (1 mL), palladiumtetrakis(triphenylphosphine (21 mg, 5 mol. %) and 4-pyridylboronic acid(54 mg, 1.2 equiv.). The reaction mixture was heated to 100° C. for 2hours and then allowed to stand at rt for 72 hours. Diluted with EA andwater, phases separated, organic phase washed with brine and dried overMgSO4. Crude material (148 mg, 96%) analyzed by TLC and LC MS and usedwithout further purification.

LRMS (M+H)⁺: 409.2

Example 468-(4-Chlorobenzyl)-4-methyl-2-(methylsulfonyl)-6-(pyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of starting material (100 mg, 0.244 mmol) and m-CPBA (84 mg, 2equiv.) in dichloromethane was stirred at rt for 3 hours. Stripped todryness and used without further purification for aminolysis. Yield 110mg, 93%.

LRMS (APCI) (M+H)⁺: 441.2

Example 478-(4-Chlorobenzyl)-2-amino-4-methyl-6-(pyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 151)

To a solution of crude product from previous experiment (sulfone, 80 mg,0.181 mmol) in THF (4 mL) was bubbled ammonia for 2 minutes and solutionallowed to stand capped at rt for 72 hours. Solvent removed underreduced pressure, residue partitioned between EA and saturated aqueoussodium bicarbonate (to remove PhCOOH from previous experiment). Organicphase washed with brined and dried over MgSO4. Material purified onflash column using 100% EA as eluent. Product obtained as yellow powder,42 mg (61%).

LRMS (APCI) m/z 378.4 (M+H)⁺

¹H NMR (400 MHz, d6-DMSO 8.55 (bs, 2H), 8.23 (s, 1H), 7.75 (d, J=5.81Hz, 2H), 7.33 (q, 4H), 5.73 (s, 2H), 5.45 (s, 2H), 2.58 (s, 3H).

¹H NMR (400 MHz, DMSO-d₆) d ppm 1.23-1.34 (m, 2H) 1.45-1.55 (m, 2H)1.89-1.98 (m, 2H) 2.55 (s, 3H) 2.70-2.82 (m, 2H) 3.48-3.60 (m, 1H)3.82-3.91 (m, 3H) 4.61 (d, J=4.29 Hz, 1H) 5.16-5.62 (m, 1H) 6.84 (d,J=8.59 Hz, 1H) 7.16 (s, 2H) 7.97 (s, 1H) 8.00 (dd, J=8.72, 2.40 Hz, 1H)8.42 (d, J=2.53 Hz, 1H)

Example 48 Trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol

A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.18 g, 8.24 mmol),trans-4-aminocyclohexanol (1.00 g, 6.60 mmol), potassium carbonate (1.82g, 13.2 mmol), and diisopropylethyl amine (1.44 mL, 8.24 mmol) indimethylacetamide (20.0 mL) was heated at 160° C. in a sealed tubeovernight. The reaction mixture was diluted with ethyl acetate,filtered, and the filtrate was concentrated. The residue was purified byflash chromatography eluting with chloroform/7 N ammonia in methanol(0.5-5%) to afford the title compound as a foamy solid (1.47 g, 99%).

LRMS (M+H)⁺: 223

¹H NMR (400 MHz, DMSO-d6) d ppm 1.14-1.24 (m, 4H) 1.77-1.86 (m, 4H) 1.97(s, 3H) 3.35-3.40 (m, 1H) 3.57-3.69 (m, 1H) 4.52 (d, J=4.55 Hz, 1H) 5.53(s, 1H) 5.73 (s, 2H) 6.43 (d, J=4.29 Hz, 1H)

Example 49Trans-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexanol

To a solution of(trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (1.33 g, 5.98mmol) in chloroform (15 mL) was added N-bromosuccinamide (1.08 g, 6.04mmol). After stirring at room temperature for 1.5 hr, the solution wasconcentrated. The residue was purified by flash chromatography elutingwith chloroform/7 N ammonia in methanol (0.5-5%) to afford the titlecompound (1.14 g, 63%).

LRMS (M+H)⁺: 301, 303

¹H NMR (400 MHz, DMSO-d6) d ppm 1.14-1.25 (m, 2H) 1.34-1.45 (m, 2H)1.74-1.85 (m, 4H) 2.17 (s, 3H) 3.34-3.43 (m, 1H) 3.79-3.89 (m, 1H) 4.55(d, J=4.55 Hz, 1H) 5.83 (d, J=8.34 Hz, 1H) 6.11 (s, 2H)

Example 50 (E)-ethyl3-(2-amino-4-(trans-4-hydroxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate

A sealed tube containingtrans-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexanol (655mg, 2.17 mmol), tri-o-tolylphosphine (298 mg, 0.979 mmol), ethylacrylate (355 uL, 3.26 mmol) and palladium (II) acetate (73 mg, 0.33mmol) in triethylamine (20 mL) was evacuated and back-filled withnitrogen (3×). The reaction mixture was heated overnight at 130° C.,filtered and concentrated. The residue was purified by flashchromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%)to afford the title compound (364 mg, 52%).

LRMS (M+H)⁺: 321

¹H NMR (400 MHz, DMSO-d6) d ppm 1.13-1.22 (m, 2H) 1.24 (t, J=7.07 Hz,3H) 1.34-1.45 (m, 2H) 1.80 (m, 4H) 2.21 (s, 3H) 3.34-3.41 (m, 1H)3.90-4.01 (m, 1H) 4.15 (q, J=7.07 Hz, 2H) 4.52 (d, J=4.55 Hz, 1H) 5.95(d, J=15.92 Hz, 1H) 6.27 (d, J=8.08 Hz, 1H) 6.37 (s, 2H) 7.58 (d,J=15.92 Hz, 1H)

Example 512-Amino-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 153)

To a solution of (E)-ethyl3-(2-amino-4-(trans-4-hydroxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate(233 mg, 0.727 mmol) in dimethylacetamide was added1,5-diazbicyclo[5,4,0]undec-5-ene (544 uL, 3.64 mmol) followed bypotassium tert-butoxide (1 M in THF, 364 uL, 364 mmol). The resultingsolution was heated at 150° C. overnight then concentrated. The residuewas purified by flash chromatography eluting with chloroform/7 N ammoniain methanol (0.5-5%). The product was then triturated with 1:1chloroform:hexane to afford the title compound (119 mg, 60%).

LRMS (M+H)⁺: 275

¹H NMR (400 MHz, DMSO-d6) d ppm 1.18-1.30 (m, 2H) 1.37-1.48 (m, 2H)1.87-1.94 (m, 2H) 2.45 (s, 3H) 2.70 (m, 2H) 3.46-3.57 (m, 1H) 4.59 (d,J=4.29 Hz, 1H) 5.08-5.61 (m, 1H) 6.13 (d, J=9.60 Hz, 1H) 7.09 (s, 2H)7.81 (d, J=9.35 Hz, 1H)

Example 522-Amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of2-amino-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(115 mg, 0.419 mmol) in dimethylformamide (2.0 mL) was addedN-bromosuccinimide (75 mg, 0.42 mmol). After stirring for 1.5 hr at roomtemperature the solution was concentrated. The residue was slurried inmethanol, filtered solids, and the filtrated was concentrated andpurified by flash chromatography eluting with chloroform/7 N ammonia inmethanol (0.5-3%). Combined solids to afford the title compound (120 mg,81%).

LRMS (M+H)⁺: 353/355

¹H NMR (400 MHz, DMSO-d6) d ppm 1.21-1.32 (m, 2H) 1.43-1.53 (m, 2H)1.86-1.96 (m, 2H) 2.48 (s, 3H) 2.59-2.71 (m, 2H) 3.46-3.57 (m, 1H) 4.62(d, J=3.03 Hz, 1H) 5.08-5.76 (m, 1H) 7.26 (s, 2H) 8.34 (s, 1H)

Example 532-Amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 152)

A flask containing2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(105 mg, 0.297 mmol), potassium carbonate (123 mg, 0.892 mmol), and2-methoxy-5-pyridine boronic acid (52 mg, 0.34 mmol) was evacuated andback-filled with nitrogen (2×). A solution of 5:1 dimethylformade:water(1.8 mL) was bubbled with argon for 15 min then added to the flaskfollowed by bis(tripehnylphosphine) palladium (II) chloride (10 mg,0.015 mmol). The flask was fitted with a cold finger, evacuated and backfilled with nitrogen (2×) then heated to 100° C. for 4 hr. The mixturewas cooled overnight, diluted with methanol and chloroform then filteredthrough a glass fiber filter to filter out palladium. The filtrate wasconcentrated and the residue was purified by flash chromatographyeluting with chloroform/7 N ammonia in methanol (0.5-6%) to afford thetitle compound (80, 71%).

LRMS (M+H)⁺: 382

¹H NMR (400 MHz, DMSO-d6) d ppm 1.23-1.34 (m, 2H) 1.45-1.55 (m, 2H)1.89-1.98 (m, 2H) 2.55 (s, 3H) 2.70-2.82 (m, 2H) 3.48-3.60 (m, 1H)3.82-3.91 (m, 3H) 4.61 (d, J=4.29 Hz, 1H) 5.16-5.62 (m, 1H) 6.84 (d,J=8.59 Hz, 1H) 7.16 (s, 2H) 7.97 (s, 1H) 8.00 (dd, J=8.72, 2.40 Hz, 1H)8.42 (d, J=2.53 Hz, 1H)

Example 546-Bromo-4-methyl-2-(methylthio)-8-((tetrahydrofuran-3-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a mixture of6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (900 mg,3.15 mmol) and 3-(bromomethyl)-tetrahydrofuran (571 mg, 3.46 mmol) inDMF was added CsCO₃ (1.13 g, 3.46 mmol). After stirred at 70° C. for 7 hand the mixture was quenched with water and extracted with t-butyl ethylether (4 times) and concentrated. The crude mixture was purified byflash chromatography, using 0-2% MeOH/CHCl₃, to give the title compound(715 mg, 61%).

LRMS: 370, 372 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) 8.25 (1H, s), 4.56 (2H, m), 3.96 (1H, dt,J=8.15, 5.68 Hz), 3.72-3.83 (2H, m), 3.66 (1H, dd, J=8.59, 5.81 Hz),2.81-2.95 (1H, m), 2.68 (3H, s), 2.62 (3H, s), 1.91-2.04 (1H, m),1.71-1.85 (1H, m).

Example 552-Amino-8-cyclobutyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(Compound 269)

To a solution of2-amino-6-bromo-8-cyclobutyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(371 mg, 1.20 mmol) in NMP (4 mL) was added CuCN (480 mg, 5.36 mmol).The mixture was sealed and heated at 220° C. for 30 min using microwaveirradiation. The mixture was poured into brine and filtered to give asolid. The aqueous phase was extracted with t-butyl methyl ether (3times), dried and evaporated. The combined solid was purification byflash chromatography, using 0 to 3% MeOH/CHCl₃, to give the titlecompound (240 mg, 78%).

LRMS: 256 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) 8.66 (1H, s), 7.77 (2H, d, J=21.47 Hz),5.68-5.85 (1H, m), 2.90-3.11 (2H, m), 2.12-2.28 (2H, m), 1.85-2.02 (1H,m), 1.62-1.80 (1H, m).

Example 562-Amino-8-cyclobutyl-4-methyl-6-(2-(trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one

A flask was charged with Pd(PPh₃)₂Cl₂ (84.2 mg, 0.120 mmol) and copperiodide (34.3 mg, 0.180 mmol). To this were added 1,4-dioxane (12 mL) anddiisopropylethylamine (0.84 mL, 4.8 mmol) via syringe.2-Amino-6-bromo-8-cyclobutyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(371 mg, 1.20 mmol) was introduced, and the resulting yellow solutionwas carefully sparged with nitrogen for 10 min. TMS-acetylene (0.50 mL,3.6 mmol) was then added via syringe, and the resulting black solutionwas stirred at 70° C. for 1 h. Solvent was removed under reducedpressure. The crude solid was purified by flash chromatography on silicagel eluting with CHCl₃ then 3% MeOH in CHCl₃ to afford the title product(322 mg).

LRMS: 327 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) 8.06 (1H, s), 7.39 (2H, s), 5.74-5.97 (1H, m),2.92-3.13 (2H, m), 2.49 (3H, s), 2.09-2.23 (2H, m), 1.86-1.97 (1H, m),1.63-1.81 (1H, m), 0.22 (9H, s).

Example 572-Amino-8-cyclobutyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 270)

To a stirred solution of2-amino-8-cyclobutyl-4-methyl-6-(2-(trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one(105 mg, 0.322 mmol) in MeOH (7 mL) was added K₂CO₃ (50 mg, 0.36 mmol)and the mixture was stirred for 5 h. LC-MS indicated completeconversion. Solvent was evaporated and the residue was purified by flashchromatography, using CHCl₃, to give the title compound (81 mg, 99%).

LRMS: 255 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) 7.95 (1H, s), 5.78-5.98 (1H, m), 5.25 (2H, s),3.31 (1H, s), 3.04-3.25 (2H, m), 2.56 (3H, s), 2.23-2.40 (2H, m),1.96-2.13 (1H, m), 1.73-1.91 (1H, m).

Example 58(4-(2-Amino-8-isopropyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-1H-1,2,3-triazol-1-yl)methyldiethylcarbamate (Compound 263)

2-amino-6-ethynyl-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(75 mg, 0.31 mmol) and azidomethyl diethylcarbamate (80 mg, 0.46 mmol)was suspended in 1:1 t-BuOH/H₂O (4 mL). To this was added saturatedcopper sulfate solution (0.05 mL) and stirring was continued for 24 h.The mixture was concentrated and diluted with 5 mL water. The mixturewas separated and the organic phase was washed with water andevaporated. Flash chromatography of the residue over silica gel, using0-5% MeOH/CHCl₃, gave the title compound (88 mg, 69%).

LRMS: 415 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) 8.67 (1H, s), 8.61 (1H, s), 7.28 (2H, br. s.),6.34 (2H, s), 5.88 (1H, br. s.), 3.10-3.29 (4H, m), 2.60 (3H, s), 1.55(6H, d, J=6.82 Hz), 1.05 (3H, t, J=6.95 Hz), 0.99 (3H, t, J=6.95 Hz).

Example 592-Amino-8-isopropyl-4-methyl-6-(1H-1,2,3-triazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 264)

To a solution of(4-(2-amino-8-isopropyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-1H-1,2,3-triazol-1-yl)methyldiethylcarbamate (38 mg, 0.092 mmol) in MeOH (0.5 mL) was added aqueousNaOH (1.0 M, 0.20 mL, 0.20 mmol) and the reaction mixture was stirred at85° C. for 2 day. There is about 90% conversion from LCMS. Solvent wasevaporated and the residue was purified by flash chromatography elutingwith MeOH/CHCl₃ (0-5%) to give the title (8 mg, 30%).

LRMS: 286 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) 8.50 (1H, br. s.), 8.38 (1H, br. s.), 7.27(2H, br. s.), 5.77-6.03 (1H, m), 2.59 (3H, s), 1.55 (6H, d, J=6.82 Hz).

Example 602-Amino-6-(2-hydroxypyrimidin-5-yl)-4-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 267)

A mixture of2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido-[2,3-d]pyrimidin-7(8H)-one(42.2 mg, 0.115 mmol), TMSI (0.10 mL, 0.70 mmol), and dry acetonitrile(2.3 mL) was heated at 82° C. for 1 h. After being cooled to roomtemperature, the mixture was treated with 20% NH₄OH solution andconcentrated. The mixture was purified by analytical group (HPLC) togive the title compound (12 mg, 30%).

LRMS: 355 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d6) 8.63 (2H, br. s.) 8.10 (1H, s) 7.23 (2H, br.s.) 5.54-5.84 (1H, m) 3.99 (2H, dd, J=11.12, 3.79 Hz) 3.36-3.53 (3H, m)2.83-3.06 (2H, m) 2.56 (3H, s) 1.46 (2H, d, J=9.85 Hz).

Example 61 5-Bromo-4-chloro-6-methylpyrimidin-2-amine

To a mixture of the 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8mmol) in dichloromethane (240 mL) was added bromine (1.88 mL, 36.6mmol). The resulting suspension was stirred at room temperature for 1.5hours. The mixture was diluted with dichloromethane (1.3 L) and washedwith saturated sodium bicarbonate (2×200 mL) and brine (200 mL), dried(MgSO₄), filtered and concentrated to afford5-bromo-4-chloro-6-methylpyrimidin-2-amine (7.5 g, 97%).

LCMS (M+H): 223

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.54 (s, 3H) 5.10 (s, 2H)

Example 625-Bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine

A flask containing a mixture of5-bromo-4-chloro-6-methylpyrimidin-2-amine (34.8 mmol), 2,5-hexanedione(6.15 mL, 52.2 mmol), and p-toluenesulfonic acid (330 mg, 1.74 mmol) intoluene (100 mL) was fitted with a Dean-stark apparatus and condenserand the mixture was heated to reflux. After refluxing overnight thesolution was cooled to room temperature and concentrated. The residuewas slurried in hexanes, filtered and the filtrate was concentrated. Theprecipitate was purified by flash chromatography eluting withhexanes/chloroform (0-50%) to afford the5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine(1.60 g, 15%). The concentrated filtrate was purified by flashchromatography eluting with hexanes/chloroform (10-40%) to afford5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine(5.22 g, 50%).

LRMS (M+H)⁺: 302

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 6H) 2.72 (s, 3H) 5.90 (s,2H)

Example 63trans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol

A mixture of 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (1.50 g, 4.99 mmol), trans-4-aminocyclohexanol hydrochloride(1.17 g, 6.24 mmol), and diisopropylethyl amine (2.61 mL, 15.0 mmol) indimethylacetamide (25.0 mL) was heated at 160° C. in a sealed tubeovernight. The reaction mixture was diluted with methyltertbutyl ether(400 mL), washed with saturated ammonia chloride (2×) and brine, dried(MgSO₄), filtered, and concentrated. The combined aqueous layers wereextracted with dichloromethane (3×150 mL), dried (MgSO₄), filtered, andconcentrated. The crude product was purified by flash chromatographyeluting with chloroform/methanol (0.5-3%) to affordtrans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol(1.76 g, 93%).

LCMS LRMS (M+H)⁺: 379/381

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2H) 1.46-1.57 (m, 2H)1.74-1.80 (m, 2H) 1.81-1.87 (m, 2H) 2.26 (s, 6H) 2.41 (s, 3H) 3.35-3.45(m, 1H) 3.86-3.96 (m, 1H) 4.57 (d, J=4.29 Hz, 1H) 5.76 (s, 2H) 6.82 (d,J=8.34 Hz, 1H)

Example 645-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine

To a cooled (0° C.) solution oftrans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol(1.45 g, 3.82 mmol) in tetrahydrofuran (40 mL) was added sodium hydride(60% dispersion in oil, 459 mg, 11.5 mmol). After 40 minutes, methyliodide was added (262 uL, 4.21 mmol) and the mixture was stirred at 0°C. for 2 hours. The ice bath was removed and continued to stir for 3hours then quenched with methanol and concentrated. The residue wasdissolved in ethyl acetate and washed with saturated ammonia chloride(2×), brine, dried (MgSO₄), filtered and concentrated. The crude productwas purified by flash chromatography eluting withhexanes/methyltertbutyl ether (5-25%) to afford5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine (1.10 g, 73%).

LRMS (M+H)⁺: 293/295

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.22 (m, 2H) 1.47-1.58 (m, 2H)1.78-1.87 (m, 2H) 1.97-2.07 (m, 2H) 2.26 (s, 6H) 2.41 (s, 3H) 3.04-3.14(m, 1H) 3.23 (s, 3H) 3.90-4.00 (m, 1H) 5.76 (s, 2H) 6.87 (d, J=8.34 Hz,1H)

Example 655-Bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine

A solution of5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine(1.07 g, 2.72 mmol) and hydroxylamine hydrochloride (945 mg, 13.6 mmol)in 10:1 ethanol:water (27.5 mL) was heated to reflux for 7 hours, thenroom temperature overnight. Another 0.5 eq of hydroxylaminehydrochloride was added and the solution was refluxed for another 4hours, then cooled to room temperature and concentrated. The crudeproduct was purified by flash chromatography eluting withchloroform/methanol (0.5-3%) to afford5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine(767 mg, 89%).

LRMS (M+H)⁺: 315/317

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.20 (m, 2H) 1.35-1.46 (m, 2H)1.78-1.88 (m, 2H) 1.96-2.04 (m, 2H) 2.17 (s, 3H) 3.03-3.14 (m, 1H) 3.23(s, 3H) 3.82-3.92 (m, 1H) 5.91 (d, J=8.34 Hz, 1H) 6.12 (s, 2H)

Example 66 (E)-ethyl3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate

In a sealed tube a solution of5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine(811 mg, 2.57 mmol) and ethyl acrylate (559 uL, 5.15 mmol) intriethylamine (25 mL) was bubbled with argon for ˜10 minutes.Tetrakis(triphenylphosphin)-palladium (0) (297 mg, 0.257 mmol) wasadded, the vial was sealed, and the reaction was heated to 130° C.overnight. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate (450 mL), washed with water, 0.1 N hydrochloric acid,brine, dried (MgSO₄), filtered and concentrated. The crude product waspurified by flash chromatography eluting with chloroform/methanol(0-10%) to afford (E)-ethyl3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate(674 mg, 78%).

LRMS (M+H)⁺: 335

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.20 (m, 2H) 1.24 (t, J=7.07 Hz,3H) 1.34-1.46 (m, 2H) 1.79-1.89 (m, 2H) 1.96-2.05 (m, 2H) 2.21 (s, 3H)3.03-3.12 (m, 1H) 3.23 (s, 3H) 3.92-4.03 (m, 1 H) 4.15 (q, J=7.07 Hz,2H) 5.96 (d, J=15.92 Hz, 1H) 6.31 (d, J=8.08 Hz, 1H) 6.37 (s, 2H) 7.59(d, J=15.92 Hz, 1H)

Example 672-Amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

A solution of (E)-ethyl3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate(674 mg, 2.02 mmol) thiophenol (621 ul, 6.05 mmol),1,5-diazabicyclo5,4,0)undec-5-ene (1.81 mL, 12.1 mmol) and triethylamine(1.69 mL, 12.1 mmol) in N′,N-dimethylformamide (15 mL) was heated in themicrowave for 30 minutes at 100° C. then in an oil bath at 100° C.overnight. The reaction mixture was diluted with methyltertbutyletherand washed with saturated sodium carbonate, brine, 0.1 N hydrochloricacid, brine, dried (MgSO₄), filtered and concentrated. The combinedaqueous layer was extracted with dichloromethane (2×). The organic layerwas dried (MgSO₄), filtered and concentrated. The crude product waspurified by flash chromatography eluting with chloroform/methanol (0-5%)to afford2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(482 mg, 83%).

LRMS (M+H)⁺: 289

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 2H) 1.45-1.55 (m, 2H)2.05-2.14 (m, 2H) 2.46 (s, 3H) 2.66-2.77 (m, 2H) 3.26 (s, 3H) 3.29-3.33(m, 1H) 4.97-5.61 (m, 1H) 6.14 (d, J=9.35 Hz, 1H) 7.11 (s, 2H) 7.82 (d,J=9.35 Hz, 1H)

Example 682-Amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(482 mg, 0.1.67 mmol) in dimethylformamide (15 mL) was addedN-bromosuccinimide (300 mg, 1.69 mmol). After stirring for 1 hour atroom temperature the solution was diluted with methyltertbutylether andwashed with 50% sodium carbonate (2×) and brine. The combined aqueouslayers were extracted with dichloromethane. The combined organics weredried (MgSO₄) filtered and concentrated. The solids were triturated withdiethyl ether to afford2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(594 mg, 97%).

LRMS (M+H)⁺: 367/369

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2H) 1.49-1.59 (m, 2H)2.06-2.15 (m, 2H) 2.49 (s, 3H) 2.61-2.73 (m, 2H) 3.17-3.26 (m, 1H) 3.27(s, 3H) 5.15-5.67 (m, 1H) 7.26 (s, 2H) 8.34 (s, 1H)

Example 692-Amino-8-(trans-4-methoxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 179)

To a vial containing2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(75 mg, 0.20 mmol), 2-methoxy-5-pyridineboronic acid (37.5 mg, 0.245mmol) and cesium carbonate was added PdCl₂(dppf)1:1 w/CH₂Cl₂ followed by5:1 dimethoxyethane:water (3 mL, degassed by bubbling with argon). Thevial was capped and heated in the microwave for 30 minutes at 100° C.The reaction mixture was concentrated and the crude product was purifiedby flash chromatography eluting with chloroform/methanol (0-5%). Thefractions containing the desired product were concentrated and thesolids were triturated with methyltertbutyl ether to afford2-amino-8-(trans-4-methoxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(33 mg, 40%).

LRMS (M+H)⁺: 396

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.28 (m, 2H) 1.52-1.62 (m, 2H)2.07-2.17 (m, 2H) 2.55 (s, 3H) 2.72-2.83 (m, 2H) 3.26 (s, 3H) 3.30-3.33(m, 1H) 3.88 (s, 3H) 5.30-5.63 (m, 1H) 6.84 (d, J=8.59 Hz, 1H) 7.17 (s,2H) 7.98 (s, 1H) 8.00 (dd, J=8.59, 2.53 Hz, 1H) 8.42 (d, J=2.53 Hz, 1H)

Example 70 Potassium 1H-pryazole-5-trifluoroborate

A mixture of 1H-pryazole-5-boronic acid (150 mg, 1.34 mmol) andpotassium hydrogen fluoride (262 mg, 3.35 mmol) in 1:3 methanol/water (2mL) was stirred at room temperature overnight. The mixture wastransferred to a vial, the vial was sealed and the mixture was heated to100° C. in an oil bath for 2 hours, resulting in a solution. Thesolution was cooled and concentrated. The solids were slurried in hotacetone, filtered, and the filtrate was concentrated to afford potassium1H-pryazole-5-trifluoroborate (234 mg, 100%).

Example 712-Amino-8-((trans)-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 186)

A mixture of2-amino-6-bromo-8-((trans)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(100 mg, 0.283 mmol), potassium 1H-pryazole-5-trifluoroborate (98.5 mg,0.566 mmol), and triethylamine (197 uL, 1.42 mmol) in ethanol (3.0 mL)was bubbled with argon. PdCl₂(dppf)1:1 w/CH₂Cl₂ was added, the vial wassealed and the mixture was bubbled with argon again, then heated in themicrowave for 30 minutes at 100° C., then 60 minutes at 150° C. Thereaction mixture was concentrated and purified by flash chromatographyeluting with 1:1 ethyl acetate:chloroform/7 N ammonia in methanol(0.5-7%). The fractions containing the desired product were combined andconcentrated and the solids were recrystallized from methanol/chloroformto afford2-amino-8-((trans)-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(32 mg, 33%).

LRMS (M+H)⁺: 341

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.35 (m, 2H) 1.44-1.55 (m, 2H)1.90-1.99 (m, 2H) 2.56 (s, 3H) 2.73-2.84 (m, 2H) 3.50-3.62 (m, 1H) 4.62(d, J=4.04 Hz, 1H) 5.12-5.74 (m, 1H) 6.93 (s, 1H) 7.14-7.26 (m, 2H) 7.62(m, 1H) 8.34 (s, 1H) 12.97 (m, 1H)

Example 721-(5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)hydrazine

To a microwave vial was added5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine(4.95 g, 16.5 mmol) and hydrazine (0.57 ml, 18.1 mmol) hunig's base95.74 ml, 32.9 mmol) and dimethyacetamide (24 ml) at R.T. After heatingin the microwave for 30 mins at 100° C. The reaction mixture wasconcentrated under reduced pressure to dryness and the residue wastrituarated with 1:1 ethyl acetate:methanol to obtain the desiredproduct as a white solid weighted 2820 mg. The mother liquor waspurified by column chromatography eluted with 30% EtOAc:hexane to givean additional batch of the desired product. Both lots were combined togive the titled compound as a white solid weighted 3620 mg 74%

¹H NMR (400 MHz, MeOD) δ ppm 2.30 (s, 6H) 2.51 (s, 3H) 5.79 (s, 2H)

Example 735-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methyl-N-(pyrrolidin-1-yl)pyrimidin-4-amine

To a flask was added1-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)hydrazine(100 mg, 0.34 mmol) 1,4-dibromobutane (0.04 ml, 0.37 mmol) hunig's base(0.18 ml, 1.01 mmol) and DMAC (1.0 ml) at R.T. After heating at 60° C.over night, the reaction mixture was cooled to R.T. and diluted withEtOAc (2 ml) the white solid was filtered and the mother liquor wasconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography eluted with 30% EtOAc:hex to give the titledcompound weighted 76 mg 64%

¹H NMR (400 MHz, MeOD) δ ppm 1.78 (ddd, J=6.95, 3.41, 3.28 Hz, 4H) 2.15(s, 6H) 2.41 (s, 3H) 2.85-2.92 (m, 4H) 5.67 (s, 2H)

Example 74N-(5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)-N-(pyrrolidin-1-yl)acrylamide

To a reaction solution of5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methyl-N-(pyrrolidin-1-yl)pyrimidin-4-amine(3.14 g, 8.97 mmol) in anhyrous methylene chloride (120 ml) and hunig'sbase (4.68 ml) was added slowly a solution of acryloyl chloride (0.80ml, 9.86 mmol) in methylene chloride (30 ml) dropwise at R.T. Afterstirring at R.T for 60 mins, the reaction mixture was concentrated underreduced pressure and the residue was purified by 120 g column elutedwith 40% ethyl acetate:hexane to give the titled product weighted 3.5 ga white solid 97%

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.77 (m, 4H) 2.28 (s, 6H) 2.70 (s,3H) 3.17-3.20 (m, 4H) 5.79 (d, J=11.12 Hz, 1H) 5.85 (s, 2H) 6.30 (dd,J=17.18, 2.02 Hz, 1H) 6.75 (bs, 1H)

Example 752-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a microwave vial was addedN-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)-N-(pyrrolidin-1-yl)acrylamide(2.0 g, 4.95 mmol) silver carbonate (2.73 g, 9.89 mmol) and anhydrousTHF (100 ml). The reaction suspension was bubbled in nitrogen for 2 minsand then added the palladium tetrakis tert-(triphenylphosphine) (286 mg,0.25 mmol). After stirring at 70° C. oil bath for 3 h, the reactionmixture was cooled to R.T. and diluted with 20 ml of brine. Afterstirring at R.T. for 5 mins, the reaction mixture was filtered through acelite pad. The cake was washed with ethyl acetate. The layers wereseparated. The organic layer was washed with brine 20 ml, dried withpotassium carbonate, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography eluted with40% etoac:hex to give the titled compound weighted 480 mg 30%

¹H NMR (400 MHz, MeOD) δ ppm 2.01-2.13 (m, 4H) 2.39 (s, 6H) 2.80 (s, 3H)3.32-3.39 (m, 4H) 5.86 (s, 2H) 6.72 (d, J=9.85 Hz, 1H) 8.15 (d, J=9.60Hz, 1H)

Example 762-Amino-4-methyl-8-pyrrolidin-1-ylpyrido[2,3-d]pyrimidin-7(8H)-one

To a microwave vial was added2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3,d]pyrimidin-7(8H)-one(530 mg, 1.64 mmol) hydroxamine hydrochloride (1.14 g, 16.4 mmol)ethanol (20 ml) and water (2.92 ml). The vial was capped and refluxed at100° C. After 3 h, the reaction mixture was concentrated to drynessunder reduced pressure and the resulting residue was purified by columnchromatography eluted with 10% 7N NH3 in MeOH:CHCl3 to give the desiredproduct weighted 296 mg 74%

LRMS (M+H)⁺: 246.1

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.00 (m, 4H) 2.47 (s, 3H) 3.16-3.24(m, 4H) 6.20 (d, J=9.60 Hz, 1H) 7.21 (br. s., 2H) 7.84 (d, J=9.60 Hz,1H)

Example 772-Amino-6-bromo-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a suspension of2-amino-4-methyl-8-pyrrolidin-1-ylpyrido[2,3-d]pyrimidin-7(8H)-one (22.0mg, 0.09 mmol) in anhydrous DMF (1.0 ml) and 0014 (1.0 ml) was added twodrops of bromine via syringe at R.T. After stirring at R.T. for 3 minsto the reaction mixture, TEA (0.08 ml) was added. After stirring for 1.5h at R.T., the reaction mixture was concentrated under reduced pressureand the resulting residue was purified by column chromatography elutedwith 10% 7N NH3 in MeOH:CHCl3 to give the titled compound 13.0 mg 45%product weighted 25 mg 45%

LCMS (APCI+) 324.0

¹H NMR (400 MHz, MeOD) δ ppm 2.02-2.14 (m, 4H) 2.57 (s, 3H) 3.32-3.38(m, 4H) 8.36 (s, 1H)

Example 782-Amino-4-methyl-6-(1H-pyrazol-4-yl)-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 193)

To a flask was added a2-amino-6-bromo-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(21.0 mg, 0.06 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(20.9 mg, 0.07 mmol) potassium carbonate (25.6 mg, 0.19 mmol) in DMAC(1.20 ml):H2O (0.1 ml). The reaction mixture was degassed by alternatingbetween N2 and vacuum. To the reaction mixture was added PdCl₂(PPh₃)₂(4.3 mg). After heating in microwave for 60 min at 100° C., the reactionmixture was concentrated under reduced pressure and the resultingresidue was purified by reversed phase column eluted with acetonitrile:0.1% acetic acid in water to give the titled compound weighted 2.5 mg

¹H NMR (400 MHz, MeOD): 2.07-2.18 (m, 4H) 2.66 (s, 3H) 3.35-3.46 (m, 4H)8.18 (s, 1H) 8.28 (bs, 2H)

Example 79Tert-butyl-4-(2-amino-4-methyl-7-oxo-8-(pyrrolidin-1-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate(Compound 192)

This titled compound was obtained from the reaction that producedexample 78, weighted 3.1 mg.

¹H NMR (400 MHz, MeOD): 1.58 (s, 9H) 2.00-2.05 (m, 4H) 2.57 (s, 3H)3.27-3.34 (m, 4H) 8.07 (s, 1H) 8.21 (s, 1H) 8.32 (s, 1H)

Example 808-Cyclopentyl-6-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

To the solution of8-Cyclopentyl-4-methyl-2-methylsulfanyl-6-(1H-pyrazol-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one(100 mg, 0.29 mmol) in 5 ml of DMSO were added 2,2-Dimethyl-oxirane(0.03 ml, 1.20 eq.), and potassium carbonate (40.5 mg, 1.00 eq.) undernitrogen. The reaction mixture was stirred at room temperature. Aftertwo hours, no reaction. The reaction mixture was heated to 100° C. for30 min. Some product was formed. It was continued heating for 1 hour.Starting material was gone. The reaction mixture was partitioned inEA/brine. EA layer was dried and concentrated. It was further purifiedby chromatography (10% MeOH/DCM). 15 mg of product was obtained at yieldof 12%.

LCMS: 414.20 (ES+)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19 (1H, s) 7.77 (2H, d, J=20.72Hz) 7.48 (1H, t) 5.78-5.96 (1H, m) 3.92 (2H, s) 2.54 (3H, s) 2.43 (3H,d, J=1.26 Hz) 2.21 (2H, s) 1.91 (2H, s) 1.70 (2H, s) 1.52 (2H, s) 1.01(6H, s)

Example 812-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-8-pyrrolidin-3-yl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 247)

The TFA (0.56 ml, 10 eq.) was added into the solution of3-[2-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]pyrrolidine-1-carboxylicacid tert-butyl ester (328 mg, 0.725 mmol) in 2 ml dichloromethane atroom temperature. The reaction mixture was stirred at room temperatureovernight. The reaction was complete and the solvent was removed. Theresidue was partitioned in EA/sat. sodium bicarbonate. The EA layer wasdried and concentrated to obtain the title compound as a solid (237 mg,92.8% yield).

LCMS: 353.20 (ES+)

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (1H, d, J=2.53 Hz) 8.07 (1H, s)8.02 (1H, dd, J=8.72, 2.40 Hz) 7.39 (2H, br. s.) 6.87 (1H, d, J=8.59 Hz)6.23-6.43 (1H, m) 3.88 (3H, s) 3.63-3.77 (2H, m) 3.36-3.45 (2H, m)3.14-3.26 (1H, m) 2.58 (3H, s) 2.24-2.37 (2H, m)

Example 828-(1-Acetyl-pyrrolidin-3-yl)-2-amin-6-(6-methoxy-pyridin-3-yl)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 248)

To the solution of2-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-8-pyrrolidin-3-yl-8H-pyrido[2,3-d]pyrimidin-7-one(100 mg, 0.284 mmol) in 5 ml DMF were added acetic acid (17 mg, 1.0eq.), HATU (108 mg, 1.0 eq.), and TEA (0.04 ml, 1.0 eq.). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas partitioned in EA/brine. The EA layer was washed with sodiumbicarbonate and brine, dried and concentrated. The residue was furtherpurified by chromatography (10% MeOH/DCM and 0.5% TEA) to give the titlecompound (37 mg, 31% yield).

LCMS: 395.20 (ES+)

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, s) 7.94-8.12 (2H, m) 7.23 (2H,br. s.) 6.85 (1H, d, J=8.59 Hz) 6.07-6.41 (1H, m) 3.83-4.08 (4H, m)3.47-3.81 (3H, m) 2.62-2.82 (4H, m) 2.53-2.62 (3H, m) 2.02-2.23 (1H, m)

Example 83Butyl-2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate

A microwave vial was charged with Mo(CO)6 (264 mg, 1.0 mmol), Herrmann'spalladacycle (23 mg, 0.025 mmol), [(t-Bu)3PH]BF4 (15 mg, 0.050 mmol),2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(353 mg, 1.0 mmol), DMF (5 mL) and butanol (5 mL). DBU (412 ml, 3.0mmol) was added, followed by rapid sealing of the vial under air. Thevial was then heated to 120° C. by microwave irradiation for 30 minutes.After cooling, the reaction mixture was slurried with water andfiltered. The precipitate was washed with ether and dried to afford 253mg of butyl2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate.

LRMS (M+H)⁺: 375

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H) 1.24-1.33 (m,2H) 1.37-1.49 (m, 4H) 1.58-1.69 (m, 3H) 1.92 (dd, J=10.74, 3.41 Hz, 3H)2.52 (s, 3H) 3.47 (s, 1H) 3.54 (s, 1H) 4.18 (t, J=6.69 Hz, 2H) 4.61 (d,J=4.55 Hz, 1H) 7.51 (s, 2H) 8.31 (s, 1H)

Example 842-Amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylicacid

A 1M solution of LiOH in H2O (0.81 mL, 0.81 mmol) was added to asuspension of butyl2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate(0.25 g, 0.68 mmol) in THF (7 mL) and MeOH (2 mL). After 2.5 h, DCM,EtOH, water, brine, celite and 0.7 mL of 1 M HCl were added. The mixturewas filtered. The organic layer was seperated and concentrated by rotaryevaporation to affored 0.25 g of2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylicacid.

LRMS (M+H)⁺: 319

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.36 (m, 3H) 1.57 (d, J=11.12 Hz,2H) 1.56 (br. s., 1H) 1.94 (t, J=9.73 Hz, 2H) 2.62 (s, 3H) 2.67 (br. s.,1H) 3.55 (br. s., 1H) 4.69 (br. s., 1H) 7.92 (d, J=8.59 Hz, 1H) 7.89 (d,J=2.78 Hz, 1H) 8.68 (s, 1H) 14.14 (br. s., 1H)

Example 852-Amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-N-1H-pyrazol-5-yl-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide(Compound 251)

HATU (105 mg, 0.28 mmol) was added to a mixture of2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylicacid (80 mg, 0.25 mmol), DMF (2.5 mL) and TEA (38 uL, 0.28 mmol). After5 min. a solution of 1H-pyrazol-5-amine (46 mg, 0.55 mmol) in DMF (0.55mL) was added. After 19 hours the mixture was diluted with water (˜10mL), centrifuged then decanted. More water was added to the precipitateand procedure was repeated. The resulting precipitate was suspended in amixture of DCM and methanol and concentrated by rotary evaporation toafford2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-N-1H-pyrazol-5-yl-78-dihydropyrido[23-d]pyrimidine-6-carboxamide(35 mg, 37%).

LRMS (M+H)⁺: 384

¹H NMR (400 MHz, DMSO-d 6) δ ppm 1.31 (q, J=12.13 Hz, 2H) 1.56 (d,J=9.85 Hz, 2H) 1.96 (d, J=8.34 Hz, 2H) 2.61 (br. s., 3H) 2.64-2.84 (m,2H) 3.58 (br. s., 1H) 4.66 (br. s., 1H) 5.54 (br. s., 1H) 6.65 (s, 1H)7.71 (d, J=5.81 Hz, 1H) 7.67 (br. s., 2H) 8.79 (s, 1H) 11.90 (s, 1H)

Example 868-Cyclopentyl-4-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

A solution of4-cyclopentylamino-6-methyl-2-methylsulfanyl-pyrimidine-5-carbaldehyde(20.8 g, 0.083 mol), piperidine (8.2 mL) and AcOH (9.4 mL) in malonicacid diethyl ester (150 mL) was stirred at 130° C. for 72 hours. TLC(petroleum ether/EtOAc 4:1) indicated about half of the startingmaterial was consumed. The reaction mixture was then concentrated invacuo and the residue was purified by column chromatography (silica gel,petroleum ether/EtOAc 4:1) to yield the title compound (11.3 g, 39.4%)as a yellow solid.

LRMS: 348 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): 8.38 (s, 1H), 5.96-5.91 (m, 1H), 4.38-4.32 (q,2H), 2.63 (s, 3H), 2.55 (s, 3H), 2.31-2.28 (m, 2H), 2.04-2.00 (m, 2H),1.83-1.75 (m, 2H), 1.62-1.58 (m, 2H), 1.36-1.32 (t, 3H)

Example 878-Cyclopentyl-2-methanesulfinyl-4-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

To a stirred solution of compound 86 (17.0 g, 0.049 mol) in CHCl₃ (200mL) was added m-CPBA (11.0 g, 0.050 mol) portion wise at 10° C. Afterthe addition, the resulting mixture was stirred at room temperature for2 hours. TLC (petroleum ether/EtOAc 2:1) indicated complete consumptionof starting material. The reaction mixture was then washed withsaturated aqueous Na₂SO₃ (100 mL×3), saturated aqueous NaHCO₃ (100 mL)and brine (100 mL) in sequence, dried over Na₂SO₄ and concentrated invacuo to give the title compound (16.0 g, 90.0%) as a yellow solid.

Example 888-Cyclopentyl-4-methyl-2-methylamino-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

A solution of example 87 (16.0 g, 0.044 mol), methylamine (10.15 g,0.088 mol, 27% in EtOH), Et₃N (8.9 g, 0.088 mol) and a catalytic amountof DMF in acetonitrile (60 mL) was refluxed for 48 hours under a N₂balloon. TLC (petroleum ether/EtOAc 1:2) indicated the starting materialwas consumed completely. The reaction mixture was then concentrated invacuo and the residue was purified by column chromatography (silica gel,petroleum ether/EtOAc from 15:1 to 4:1) to yield the crude product.Re-crystallization from CH₂Cl₂/petroleum ether (10 mL/150 mL) affordedpure title compound (10.5 g, 72.2%) as a white solid.

Example 898-Cyclopentyl-4-methyl-2-methylamino-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid

A solution of example 88 (10.5 g, 0.032 mol) and LiOH H₂O (2.67 g, 0.064mol) in EtOH (350 mL) and water (50 mL) was stirred at room temperatureovernight. TLC (petroleum ether/EtOAc 1:2) indicated completeconsumption of starting material. EtOH was removed in vacuo and theresidue was acidified to pH˜5 by 1 N aqueous HCl (20 mL). The resultingmixture was filtered. The cake was washed with petroleum ether (100mL×3) and dried in vacuo to give the title compound (6.53 g, 68.0%) as awhite solid.

LRMS: 303 (M+H)⁺.

¹H NMR (400 MHz, DMSO): 8.59 (s, 1H), 8.12-7.87 (d, 1H), 6.00-5.97 (m,1H), 2.89 (s, 3H), 2.61-2.56 (d, 3H), 2.31-2.17 (m, 2H), 2.05-1.90 (m,2H), 1.83-1.70 (m, 2H), 1.70-1.52 (m, 2H)

Example 908-Cyclopentyl-4-methyl-2-methylamino-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylicacid (1H-pyrazol-3-yl)-amide (Compound 250)

To 110 μL of 0.1 M solution of example 89 in DMF in a test tube (10×95mm) was added 100 μL of 0.1 M solution of 3-aminopyrazole in DMFfollowed by 110 μL each of 0.1 M solution of HATU and triethylamine,respectively. The reaction mixture was stirred at 80° C. for 8 h. Afterthe removal of the solvent in vacuo, the residue was reconstituted in1.2 mL of DMSO and subjected to HPLC purification to obtain the titlecompound.

LRMS: 368 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆): 11.89 (s, 1H) 8.78 (s, 1H) 8.11 (s, 1H) 7.63(s, 1H) 6.64 (s, 1H) 5.95-6.05 (m, 1H) 2.92 (s, 3H) 1.96-2.14 (m, 2H)1.74-1.94 (m, 2H) 1.54-1.74 (m, 2H).

Example 912-(2,2-Difluoroethylamino)-8-(4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 275)

To a solution of2-amino-8-(4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-[7(8H)-one(50 mg, 0.13 mmol) in anhydrous DMA (1.0 ml) at room temperature wasadded a 1M solution of potassium tert-butoxide in THF (0.14 ml). Afterstirring at R.T. for 1 hour, to the reaction mixture was added1-bromo-2,2-difluoroethane (20.9 mg, 0.14 mmol). After stirring at roomtemperature for 16 h and 4.5 h at 80° C. the reaction mixture was cooledto room temperature, and 1M solution of potassium tert-butoxide in THF(0.16 ml) and 1-bromo-2,2-difluoroethane (41.8 mg, 0.28 mmol) wereadded. After stirring at 80° C. for 16 h, to the reaction mixture wasadded another 1M solution of potassium tert-butoxide in THF (0.1 ml) and1-bromo-2,2difluoroethane (62.7 mg, 0.42 mmol). After stirring at 80° C.for 16 h, to the reaction mixture another 3 eq of 1M solution ofpotassium tert-butoxide in THF and 3 eq of 1-bromo-2,2-difluoroethanewere added. After heating in microwave for 20 mins at 120° C., thereaction mixture was cooled to room temperature and diluted with DMSO,the precipitate was removed by filtration. The filtrate was combined andpurified using reversed phase column eluted with acetonitrile (0.1%acetic acid) and water (0.1% acetic acid) to give the titled compound asa solid weighted 14.6 mg.

LCMS (APCI+1) 446.3.

¹H NMR (400 MHz, MeOD): 1.38-1.54 (m, 2H) 1.61-1.76 (m, 2H) 2.04-2.15(m, 2H) 2.84 (br. s., 2H) 3.63-3.72 (m, 1H) 3.86 (t, J=14.53 Hz, 2H)3.94 (s, 3H) 5.58 (br. s., 1H) 6.05 (t, J=56.08 Hz, 1H) 6.82 (d, J=8.59Hz, 1H) 7.91-7.99 (m, 2H) 8.33-8.41 (m, 1H).

Example 92trans-4-(2-Amino-5-iodo-6-methylpyrimidin-4-ylamino)cyclohexanol Step 1:Synthesis of trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol

A suspension mixture of 2-amino-4-chloro-6-methylpyrimidine (144 g, 1.0mol), trans-4-aminocyclohexanol (140 g, 1.2 mol), AcOH (5 mL) in water(0.6 L) was heated at 99° C. in a 3.0 L flask. After 6 h at sametemperature, Sodium acetate (82.0 g, 1 mol) was added to the reactionmixture. After 48 h, at the same temperature aq NaOH (50 mL, 10 N) wasadded. The reaction mixture was heated to 99° C. for 2 additional days.The reaction can be stopped if 2-amino-4-chloro-6-methylpyrimidine isless than 2% by HPLC analysis. If the reaction is slow another portionof aq. NaOH can be added to the reaction mixture as long as the pH is ˜7to 8. The reaction mixture was then neutralized with Sodium bicarbonateand cooled to 0° C. Filtration gavetrans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (˜85%). Wetmaterial is used for next step.

¹H NMR (300 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 4H) 1.77-1.86 (m, 4H) 1.97(s, 3H) 3.35-3.40 (m, 1H) 3.57-3.69 (m, 1H) 4.52 (d, J=4.55 Hz, 1H) 5.53(s, 1H) 5.73 (s, 2H) 6.43 (d, J=4.29 Hz, 1H) (M+H)⁺223

Step 2: Synthesis oftrans-4-(2-amino-5-iodo-6-methylpyrimidin-4-ylamino)cyclohexanol

To a slurry of(1r,4r)-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (58 g, 0.26mol) in water (0.5 L) was added slowly 1.0 equivalent ofN-iodosuccinimide (59 g, 0.26 mol) at 10° C. over several hours. Afterstirring at 10° C. for 4 h, the reaction mixture was stirred overnightand heated to 40° C. for several hours. The suspension mixture was thencooled to rt, quenched with NaHSO₃. 0.8 Equivalent of NaOH was added(form the sodium succinimide) and the product was filtered to give 100 gof wet product. The product was purified by slurry witht-butylmethylether and recrystallization in 100 mL methanol and dried toprovide puretrans-4-(2-amino-5-iodo-6-methylpyrimidin-4-ylamino)cyclohexanol (65 g,72% yield).

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.45 (m, 4H) 1.74-1.90 (m, 4H) 2.21(s, 3H) 3.34-3.43 (m, 1H) 3.79-3.91 (m, 1H) 4.55 (d, J=4.55 Hz, 1H) 5.40(d, J=8.34 Hz, 1H) 6.11 (s, 2H)

(M+H)⁺349

Example 932-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 152) Step 1: Preparation of (E)-ethyl3-(2-amino-4-(trans-4-hydroxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate

Materials:

trans-4-(2-amino-5-iodo-6-methylpyrimidin-4- 35 g, 0.1 mol, 1.0 eq.ylamino)cyclohexanol Ethyl acrylate (FW = 100, d = 0.918) 22 mL, 0.2mol, 2.0 eq. Palladium acetate (FW = 224.5) 675 mg, 3 mmol, 0.03 eq.Triethylamine (FW = 101, d = 0.726) 28 mL, 0.2 mol, 2.0 eq. DMF 80 mLProcedure:

-   1. Equip a 500 mL, 3-neck round bottom flask into a heating mantle    with a mechanical stirrer, additional funnel, thermocouple and    nitrogen inlet.-   2. Charge the flask with    trans-4-(2-amino-5-iodo-6-methylpyrimidin-4-ylamino)cyclohexanol (35    g), DMF (80 mL), Palladium acetate (675 mg), ethyl acetate (22 mL),    and triethylamine (28 mL) and the reaction was heated with stirring    at ˜90° C. for 6 hours. HPLC analysis indicated the disappearance of    the starting material and the reaction is considered completed. The    reaction mixture was filtered through charcoal, celite and Silicycle    to remove most of the Palladium black. Extraction of the filtrate    with heptane (2×100 mL) removed the remaining ethyl acetate and    triethylamine. The DMF fraction was subjected to Rotovap    distillation to remove remaining ethyl acrylate. The remaining DMF    solution (˜150 mL) was used directly in next step without any    purification.

Step 2: Preparation of2-amino-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Materials:

2-amino-8-(trans-4-hydroxycyclohexyl)-4- 150 mL solution, 1.0 eq.methylpyrido[2,3-d]pyrimidin-7(8H)-one solution PhSNa (FW = 132) 13.2 g,0.1 mol, 1.0 eq. PhSH (FW = 110, d = 1.078) 11 mL, 0.1 mol, 1.0 eq. DBU(FW = 152, d = 1.018) 61 mL, 0.4 mol, 4.0 eq. Diisopropylethylamine (FW= 129.24, 100 mL, 0.6 mol, 6.0 eq. d = 0.782) Dimethylformide 100 mLProcedure:

-   1. Equip a 500 mL, 3-neck round bottom flask with a mechanical    stirrer, thermocouple, addition funnel, nitrogen inlet and    distillation set into a heating mantle.-   2. Charge the flask with the DMF solution from last step, PhSNa    (13.2 g), PhSH (11 mL), DBU (61 mL), Diisopropylethylamine, and DMF    (100 mL). The reaction mixture was heated at 110° C. for 3 hours.    HPLC analysis indicated the disappearance of the starting material    and the reaction was considered completed.-   3. The DMF solution was concentrated under high vacuum (5 psi) at    55° C. to give ˜150 mL of solution, which was washed with 500 mL of    t-butyl methyl ether. The ether layer was separated. 100 mL of MeOH,    600 mL of water, and 300 mL of Toluene were added to the reaction    mixture, which was stirred overnight under air. Filtration gave wet    crude    2-amino-8-((1r,4r)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one    which was directly used in next step (16 g, 50%, crude)

Step 3: Preparation of2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Materials:

2-amino-8-((1r,4r)-4-hydroxycyclohexyl)-4- 11.0 g, 34 mmol, 1.0 eq.methylpyrido[2,3-d]pyrimidin-7(8H)-one (FW = 321) N-bromosuccinimide (FW= 178) 9.2 g, 52 mmol, 1.2 eq. Acetonitrile/water (1:1) 200 mLProcedure:

-   -   1. Equip a 500 mL, round bottom flask with a mechanical stirrer    -   2. To a solution of        2-amino-8-((1r,4r)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one        (11.0 g, 34 mmol) in 1:1 acetonitrile/water (200 mL) was added        N-bromosuccinimide (9.2 g, 52 mmol). After stirring for 6 hours        at room temperature the solution was concentrated. Filtration        gave the crude product.    -   3. The crude product was slurried in 50 mL of t-butyl methyl        ether. Filtration gave        2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one        in high purity (˜8 g, 70%).

Step 4: Preparation of2-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 152)

Materials:

2-amino-6-bromo-8-(trans-4- 13.2 g, 37.38 mmol, 1.0 eq.hydroxycyclohexyl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one (FW =353.21) 6-methoxypyridin-3-ylboronic acid 7.15 g, 46.7 mol, 1.25 eq. (FW= 152.94) Cs₂CO₃ (FW = 325.8) 36.5 g 112.14 mmol, 3.0 eq. PdCl₂(PPh₃)₂(FW = 816.6) 916 mg, 1.12 mmol, 0.03 eq. 1,2-dimethoxyethane (DME)/water240 mL/50 mLProcedure:

-   -   1. Equip a 1 L, 3-neck round bottom flask into a heating mantle        with a mechanical stirrer, reflux condenser, drying tube,        thermocouple and nitrogen inlet.    -   2. Charge the flask with        2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one        (13.2 g), 6-methoxypyridin-3-ylboronic acid to boronic (7.15 g),        Cs₂CO₃ (36.5 g), PdCl₂(PPh₃)₂ (916 mg), and 1,2-dimethoxyethane        (DME)/water (240 mL/50 mL), The reaction mixture was heated to        reflux at 80° C. for 2 hours. HPLC analysis indicated the        disappearance of the starting material and the reaction was        considered completed.    -   3. The reaction mixture was cooled to room temperature.        Filtration removes the insoluble inorganic salts. The inorganic        filter cake was vigorously washed with hot THF, combined with        filtrate. Aqueous layer was separated and extract THF. THF was        evaporated and dry ethanol was added and then evaporated to give        a dark solid. The solid were dissolved in 400 mL of THF and        heated at 80° C. with 60 g of Silicycle. Filtration and        concentration of THF gave the crude final product.    -   4. The crude product (12.0 g) was slurried in 20 mL of THF and        150 mL of methanol and then heated to reflux for 30 min. The        sample was allowed to slowly cool down to 23° C. overnight. The        solids were collected by filtration and dried at 55° C. under        high vacuum to obtain 9.0 g of        2-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one        (Compound 152). The compound purity was confirmed by HPLC to be        94%.

Example 94cis-4-(5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol

A mixture of5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine(5.00 g, 17.0 mmol), cis-4-aminocyclohexanol hydrochloride (2.77 g, 18.3mmol), and diisopropylethyl amine (8.69 mL, 49.9 mmol) indimethylacetamide (60.0 mL) was heated at 160° C. in a sealed tubeovernight. The reaction mixture was concentrated and the residue waspurified by flash chromatography eluting with chloroform/methanol(0-3%). Combined fractions containing the desired product wereconcentrated. The resulting gum was dissolved in methyl tert-butyl ether(450 mL) and the solution was washed with 50% brine, dried (MgSO₄),filtered and concentrated to afford the title compound as a orange foamysolid (5.53 g, 88%).

(M+H)⁺379, 381

1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.57 (m, 4H) 1.59-1.69 (m, 2H)1.79-1.90 (m, 2H) 2.25 (s, 6H) 2.41 (s, 3H) 3.77 (d, J=2.27 Hz, 1H)3.90-4.00 (m, 1H) 4.40 (d, J=2.78 Hz, 1H) 5.75 (s, 2H) 6.74 (d, J=8.08Hz, 1H)

Example 952-cis-4-(5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol

To a cooled (0° C.) solution ofcis-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol(2.50 g, 6.59 mmol) in dimethylformamide (17.0 mL) was added sodiumhydride (60% dispersion in oil, 527 mg, 13.2 mmol). After 2.5 hr at 0°C. a solution of 1,3,2-dioxathiolane 2,2 dioxane (1.23 g, 9.89 mmol) indimethylformamide (7.0 mL) was added drop wise over 1 hr. After stirring0° C. overnight an additional 4 eq sodium hydride was added followed by1,3,2-dioxathiolane 2,2 dioxane in 0.25 eq portions every 15 min up to2.25 eq. The reaction was quenched with methanol and concentrated. Theresidue was then diluted with 1,4 dioxane (200 ml) and water (5.0 ml).p-Toluenesulfonic acid (g mmol) was added and the mixture was heated to40° C. for 1.5 hour. The solution cooled to 0° C. and saturated withsolid sodium bicarbonate. Diluted with water (100 mL) and extracted withdichloromethane (3×500 mL). Combined organics were washed with brine(150 mL), dried (MgSO₄), filtered, and concentrated. The crude productwas purified by flash chromatography eluting with hexanes/methyltert-butylether (15-75%) to afford the title compound (1.27 g, 45%).

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 2H) 1.51-1.61 (m, 2H)1.72-1.80 (m, 2H) 1.80-1.88 (m, 2H) 2.26 (s, 6H) 2.41 (s, 3H) 3.39 (t,J=5.43 Hz, 2H) 3.48-3.57 (m, 3H) 3.94-4.03 (m, 1H) 4.50 (t, J=5.56 Hz,1H) 5.75 (s, 2H) 6.80 (d, J=8.08 Hz, 1H)

(M+H)⁺424

Example 962-(cis-4-(2-Amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol

A solution of2-(cis-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol(1.23 g, 2.91 mmol) and hydroxylamine hydrochloride (1.01 g, 14.5 mmol)in 10:1 ethanol:water (22.0 mL) was heated to reflux overnight. Thereaction mixture was concentrated and the residue was purified by flashchromatography eluting with chloroform/7 N ammonia in methanol (0-4%) toafford the title compound (697 mg, 70%).

(M+H)⁺345, 347

1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.50 (m, 2H) 1.51-1.60 (m, 2H)1.60-1.70 (m, 2H) 1.72-1.81 (m, 2H) 2.17 (s, 3H) 3.38 (t, J=5.43 Hz, 2H)3.44-3.47 (m, 1H) 3.49 (q, J=5.39 Hz, 2H) 3.86-3.96 (m, 1H) 4.50 (t,J=5.68 Hz, 1H) 5.76 (d, J=8.08 Hz, 1H) 6.09 (s, 2H)

Example 97 (E)-Ethyl3-(2-amino-4-(cis-4-(2-hydroxyethoxy)cyclohexylamino)-6-methylpyrimidin-5-yl)acrylate

In a sealed tube a solution of2-(cis-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol(695 mg, 4.03 mmol) and ethyl acrylate (438 uL, 4.03 mmol) intriethylamine (10 mL) was bubbled with argon for ˜5 minutes.Tetrakis(triphenylphosphin)-palladium (0) (232 mg, 0.201 mmol) wasadded, the vial was sealed and the mixture was bubbled again with argon(5 minutes). The reaction was heated to 130° C. overnight, cooled toroom temperature and concentrated. The residue was dissolved inchloroform (500 mL) and washed with water and brine, dried (MgSO₄),filtered and concentrated. The crude product was purified by flashchromatography eluting with chloroform/7 N ammonia in methanol (0-4%) toafford the title compound (615 mg, 84%).

(M+H)⁺365

1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.07 Hz, 3H) 1.38-1.48 (m,2H) 1.51-1.59 (m, 2H) 1.62-1.73 (m, 2H) 1.77-1.86 (m, 2H) 2.21 (s, 3H)3.39 (t, J=5.43 Hz, 2H) 3.47-3.53 (m, 3H) 3.97-4.06 (m, 1H) 4.15 (q,J=7.07 Hz, 2H) 4.50 (t, J=5.56 Hz, 1H) 5.95 (d, J=15.92 Hz, 1H)6.30-6.37 (m, 3H) 7.61 (d, J=15.92 Hz, 1H)

Example 982-Amino-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

A solution of (E)-ethyl3-(2-amino-4-(cis-4-(2-hydroxyethoxy)cyclohexylamino)-6-methylpyrimidin-5-yl)acrylate(615 mg, 1.69 mmol), thiophenol (173 ul, 1.69 mmol), benzenethiol,sodium salt (248 mg, 1.69 mmol), 1,5-diazabicyclo5,4,0)undec-5-ene (1.01mL, 6.75 mmol) and diisopropylethyl amine (1.76 mL, 10.1 mmol) inN′,N-dimethylformamide (11.2 mL) was heated to 120° C. overnight. Thereaction mixture was concentrated and the residue was partitionedbetween methyl tert-butylether (500 mL) and saturated sodium bicarbonate(50 mL). The organic layer was separated and washed with 50% brine,dried (Na₂SO₄), filtered and concentrated. The combined aqueous layerswere extracted with chloroform (3×175 mL). Combined extracts were washedwith brine (50 mL), dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by flash chromatography eluting with chloroform/7Nammonia in methanol (0-6%) to afford the title compound (411 mg, 77%).

(M+H)⁺319

1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2H) 1.35-1.50 (m, 2H)1.91-2.04 (m, 2H) 2.46 (s, 3H) 2.83-3.13 (m, 2H) 3.41 (t, J=5.09 Hz, 2H)3.50-3.61 (m, 3H) 4.65 (t, J=15.26 Hz, 1H) 5.26-5.43 (m, 1H) 6.14 (d,J=9.42 Hz, 1H) 6.86-7.15 (m, 2H) 7.81 (d, J=9.42 Hz, 1H)

Example 992-Amino-6-bromo-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 284)

To a solution of2-amino-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(411 mg, 1.29 mmol) in dimethylformamide (10 mL) was addedN-bromosuccinimide (253 mg, 1.42 mmol). After stirring for 1 hour atroom temperature the solution was concentrated. The residue wasdissolved in chloroform (250 mL) and washed with 1 N sodium carbonate(2×25 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was purified by flashchromatography eluting with 1:1 ethyl acetate:chloroform/7N ammonia inmethanol (0-4%) to afford the title compound (382 mg, 75%).

(M+H)⁺397, 399

1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.31 (m, 2H) 1.37-1.48 (m, 2H)1.94-2.04 (m, 2H) 2.49 (s, 3H) 2.78-3.03 (m, 2H) 3.42 (t, J=5.31 Hz, 2H)3.53-3.61 (m, 3H) 4.53-4.79 (m, 1H) 5.33-5.56 (m, 1H) 7.08-7.32 (m, 2H)8.33 (s, 1H)

Example 1002-Amino-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 285)

A mixture of2-amino-6-bromo-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(50 mg, 0.13 mmol), potassium carbonate (52 mg, 0.38 mmol), and2-methoxy-5-pyridine boronic acid (38 mg, 0.25 mmol) in 5:1dimethylformade:water (1.3 mL) was bubbled with argon for 5 minutes. Tothe mixture was added bis(tripehnylphosphine) palladium (II) chloride (9mg, 0.13 mmol) and the microwave vial was immediately sealed and themixture was bubbled again with argon. After heating for 20 min at 100°C. in the microwave, the mixture was concentrated in vacuo. The residuewas dissolved in CHCl₃ (60 mL) and washed with water (10 mL) and brine(10 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by flash chromatographyeluting with chloroform/7 N ammonia in methanol (0-5%) to afford thetitle compound (50 mg, 93%).

(M+H)⁺426

1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.33 (m, 2H) 1.39-1.50 (m, 2H)1.95-2.04 (m, 2H) 2.55 (s, 3H) 2.89-3.12 (m, 2H) 3.42 (t, J=5.18 Hz, 2H)3.52-3.61 (m, 3H) 3.88 (s, 3H) 4.52-4.79 (m, 1H) 5.37-5.55 (m, 1H) 6.85(d, J=8.59 Hz, 1H) 6.97-7.20 (m, 2H) 7.97 (s, 1H) 8.00 (dd, J=8.72, 2.40Hz, 1H) 8.42 (d, J=2.02 Hz, 1H)

TABLE 1 Syn- thetic Method Com- (% Compound LRMS pound Yield) StructureName m/z ¹H NMR 102 D

2-amino-6-(5- aminopyrazin-2-yl)-8- cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 338 (M + H)⁺ ¹H NMR (CDCl₃, 400 MHz): 8.90 (d, J =1.52 Hz, 1H), 8.39 (s, 1H), 7.97 (d, J = 1.52 Hz, 1H), 7.18 (s, 2H),6.56 (s, 2H), 6.11-5.94 (m, 1H), 2.55 (s, 3H), 2.26 (dd, J = 11.12, 7.58Hz, 2H), 2.11- 1.98 (m, 2H), 1.83-1.71 (m, 2H), 1.66-1.54 (m, 2H). 103 C(20%)

6-(5-amino-6-{[(2S)-2- aminopropyl]oxy} pyrazin-2-yl)- 8-cyclopentyl-4-methyl-2- (methylamino)pyrido [2,3-d]pyrimidin- 7(8H)-one 425 (M + H)⁺¹H NMR (DMSO-d6, 400 MHz): 8.65 (1H, s), 8.44 (1H, s), 7.28-7.81 (1H,m), 6.60 (2H, s), 5.78-6.20 (1H, m), 4.32 (1H, dd, J = 10.48, 4.17 Hz),4.07 (1H, dd, J = 10.36, 7.07 Hz), 2.89 (3H, d, J = 4.55 Hz), 2.53-2.69(3H, m), 1.52-2.46 (11H, m), 1.14 (3H, d, J = 6.57 Hz). 108 A (50%)

8-cyclopentyl-6-(4- hydroxy-3- methoxyphenyl)-4- methyl-2-(methylamino)pyrido [2,3-d]pyrimidin- 7(8H)-one 381 (M + H)⁺ ¹H NMR(DMSO-d₆, 400 MHz): 9.06 (1H, s), 7.84 (1H, s), 7.61 (1H, m), 7.25 (1H,s), 7.10 (1H, m), 6.87-6.88 (1H, m), 5.96 (1H, m), 3.80 (3H, s), 2.88(3H, m), 2.55 (3H, s), 2.24 (2H, bm), 2.02 (2H, bm), 1.76 (2H, bm), 1.63(2H, bm). 110 E

8-allyl-6-(6- methoxypyridin-3-yl)- 4-methyl-2- (methylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one (400 MHz, CHLOROFORM- d) δ ppm 2.59 (s, 3H)3.09 (d, J = 5.05 Hz, 3H) 3.98 (s, 3H) 5.09 (s, 2H) 5.19 (d, J = 9.60Hz, 1H) 5.24-5.48 (m, 2H) 5.89-6.14 (m, 1H) 6.80 (d, J = 8.84 Hz, 1H)7.79 (s, 1H) 8.03 (dd, J = 8.72, 2.40 Hz, 1H) 8.35 (d, J = 2.27 Hz, 1H)111 A (55%)

2-amino-8- cyclopentyl-6-(6- methoxypyridin-3-yl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 352 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.43 (1H,s), 8.02 (1H, m), 7.99 (1H, s), 7.17 (2H, bs), 6.86-6.84 (1H, m), 6.02-5.98 (1H, m), 3.88 (3H, s), 2.56 (3H, s), 2.24-2.23 (2H, bm), 2.02 (2H,bm), 1.76 (2H, bm), 1.59 (2H, bm). 112 A (75%)

2-amino-6-(6- chloropyridin-3-yl)-8- cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 356 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.70 (1H,s), 8.15 (1H, s), 7.57 (2H, m), 7.33 (2H, bs), 6.00 (1H, m), 2.59 (3H,s), 2.23 (2H, bm), 2.02 (2H, bm), 1.76 (2H, bm), 1.59 (2H, bm). 115 A(58%)

8-cyclopentyl-4- methyl-2- (methylamino)-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 375 (M + H)⁺ ¹H NMR (DMSO-d₆, 400MHz): 8.47 (1H, s), 8.23 (1H, s), 8.00 (1H, s), 7.49 (1H, d), 7.14 (2H,bs), 6.49 (1H, m), 6.04 (1H, m), 2.98 (3H, s), 2.55 (3H, s), 2.28-2.23(2H, bm), 2.03 (2H, bm), 1.78 (2H, bm), 1.59 (2H, bm). 117 B (4.6%)

3-[8-cyclopentyl-2- (ethylamino)-4-methyl- 7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl]-N,N- diethylpropanamide 400 (M + H)⁺ ¹H NMR (MeOD, 400MHz) 7.75 (s, 1H) 5.89-6.21 (m, 1H) 3.46 (q, J = 7.30 Hz, 2H) 3.32-3.41(m, 4H) 2.83 (t, J = 7.30 Hz, 2H) 2.67 (t, J = 7.18 Hz, 2H) 2.54 (s, 3H)2.29-2.46 (m, 2H) 1.99- 2.15 (m, 2H) 1.77-1.89 (m, 2H) 1.61-1.76 (m, 2H)1.23 (t, J = 7.18 Hz, 3H) 1.14 (t, J = 7.05 Hz, 3H) 1.06 (t, J = 7.05Hz, 3H). 118 B (27%)

3-[8-cyclopentyl-2- (ethylamino)-4-methyl- 7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl]propanamide 344 (M + H)⁺ ¹H NMR (MeOD, 400 MHz) 7.76(s, 1H) 5.89-6.16 (m, 1H) 3.46 (q, J = 7.30 Hz, 2H) 2.82 (t, J = 7.43Hz, 2H) 2.54 (s, 3H) 2.51 (t, J = 7.55 Hz, 2H) 2.29-2.44 (m, 2H) 2.01-2.13 (m, 2H) 1.76-1.89 (m, 2H) 1.62-1.75 (m, 2H) 1.23 (t, J = 7.18 Hz,3H). 119 B (3.6%)

3-[8-cyclopentyl-2- (ethylamino)-4-methyl- 7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl]-N- 1H-imidazol-2- ylpropanamide 410 (M + H)⁺ ¹H NMR(MeOD, 400 MHz) 7.78 (s, 1H) 6.79 (s, 2H) 5.91-6.16 (m, 1H) 3.42- 3.52(m, 3H) 2.86-2.96 (m, 2H) 2.71 (t, J = 7.55 Hz, 3H) 2.50 (s, 3H)2.31-2.47 (m, 2H) 2.00-2.14 (m, 2H) 1.84 (d, J = 5.29 Hz, 2H) 1.62- 1.76(m, 2H) 1.23 (t, J = 7.18 Hz, 3H). 122 B (9.0%)

3-[8-cyclopentyl-2- (ethylamino)-4-methyl- 7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl]-N- pyridin-2- ylpropanamide 421 (M + H)⁺ ¹H NMR (MeOD,400 MHz) 8.26 (dd, J = 4.78, 1.01 Hz, 1H) 8.07 (d, J = 8.31 Hz, 1H) 7.79(s, 1H) 7.71-7.78 (m, 1H) 7.04-7.12 (m, 1H) 5.98- 6.15 (m, 1H) 3.40-3.51(m, 2H) 2.92 (t, J = 7.43 Hz, 2H) 2.73 (t, J = 7.43 Hz, 2H) 2.50 (s, 3H)2.38 (s, 2H) 1.99- 2.14 (m, 2H) 1.77-1.90 (m, 2H) 1.61-1.76 (m, 2H) 1.23(t, J = 7.30 Hz, 3H). 124 A (35%)

8-cyclopentyl-4- methyl-2- (methylamino)-6-(1H- pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 325 (M + H)⁺ ¹H NMR (DMSO-d₆, 400MHz): 8.26 (2H, bs), 8.13 (1H, s), 7.09 (2H, bs), 6.02- 5.99 (1H, m),2.87 (3H, s), 2.59 (3H, s), 2.27-2.23 (2H, bm), 2.01 (2H, bm), 1.77-1.74 (2H, bm), 1.63 (2H, bm). 125 A (88%)

2-amino-6-(2- aminopyridin-3-yl)-8- cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 352 (M + H)⁺ ¹H NMR (CDCl₃, 400 MHz): 7.98-7.96(1H, m), 7.96 (1H, s), 7.71-7.69 (1H, m), 6.86- 6.82 (1H, m), 6.00-5.96(1H, m), 2.51 (3H, s), 2.25-2.18 (2H, bm), 1.98 (2H, bm), 1.75-1.71 (2H,bm), 1.56- 1.54 (2H, bm). 126 A (40%)

2-amino-8- cyclopentyl-6-(2- methoxypyridin-3-yl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 352 (M + H)⁺ ¹H NMR (CDCl₃, 400 MHz): 8.09-8.08(1H, m), 7.75 (1H, s), 7.45-7.43 (1H, m), 6.78- 6.75 (1H, m), 6.08 (1H,bs), 5.11 (1H, bs), 3.09 (3H, s), 2.55 (3H, s), 2.41 (2H, bm), 2.08 (2H,bm), 1.90-1.85 (2H, bm), 1.69-1.66 (2H, bm). 127 A (60%)

2-amino-8- cyclopentyl-4-methyl- 6-(1H-pyrrolo[2,3- b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 361 (M + H)⁺ ¹H NMR (DMSO-d₆, 400MHz): 8.46 (1H, s), 8.23 (1H, s), 8.00 (1H, s), 7.49 (1H, d), 7.14 (2H,bs), 6.49 (1H, m), 6.04 (1H, m), 2.58 (3H, s), 2.28-2.23 (2H, bm), 2.03(2H, bm), 1.78 (2H, bm), 1.59 (2H, bm). 128 A (85%)

8-cyclopentyl-6-(2- methoxypyridin-3-yl)- 4-methyl-2-(methylamino)pyrido [2,3-d]pyrimidin- 7(8H)-one 366 (M + H)⁺ ¹H NMR(CDCl₃, 400 MHz): 8.17-8.15 (1H, m), 7.80 (1H, s), 7.74-7.72 (1H, m),6.98- 6.94 (1H, m), 6.04 (1H, bs), 3.95 (3H, s), 3.09-3.07 (3H, m), 2.55(3H, s), 2.41 (2H, bm), 2.01 (2H, bm), 1.90- 1.85 (2H, bm), 1.69-1.66(2H, bm). 131 A (65%)

6-(2-aminopyridin-3- yl)-8-cyclopentyl-2- (ethylamino)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 365 (M + H)⁺ ¹H NMR (CDCl₃, 400MHz): 7.98-7.96 (1H, m), 7.94 (1H, s), 7.63 (1H, m), 6.82-6.79 (1H, m),5.93 (1H, m), 3.34 (2H, m), 2.51 (3H, s), 2.35- 2.34 (2H, bm), 1.95 (2H,bm), 1.91 (2H, bm), 1.61 (2H, bm), 1.15 (3H, t). 134 A

8-cyclopentyl-6-(3- fluoropyridin-2-yl)-4- methyl-2- (methylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one 354 (M + H)⁺ ¹H NMR (CDCl₃, 400 MHz):8.49-8.48 (1H, m), 8.06 (1H, s), 7.84 (0.7H, b) 7.76 (1H, m), 7.65(0.3H, b), 7.54-7.48 (1H, m), 6.03-5.90 (1H, m), 2.90 (3H, d, J = 4.3Hz), 2.60-2.50 (4H, burried m), 2.40-2.10 (2H, bm), 2.00- 1.91 (2H, bm),1.85-1.75 (2H, bm), 1.67-1.54 (2H, bm). 135 A (18%)

8-cyclopentyl-2- (ethylamino)-4-methyl- 6-(1H-pyrrolo[2,3- b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 389 (M + H)⁺ ¹H NMR (DMSO-d₆, 400MHz): 8.46 (1H, s), 8.22 (1H, s), 7.99 (1H, s), 7.47 (1H, d), 6.49-6.47(1H, m), 6.00 (1H, m), 3.34 (2H, m), 2.51 (3H, s), 2.28-2.23 (2H, bm),1.99 (2H, bm), 1.79 (2H, bm), 1.64 (2H, bm), 1.17 (3H, t). 136 A (51%)

8-cyclopentyl-2- (ethylamino)-6-(4- hydroxy-3- methoxyphenyl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 396 (M + H)⁺ ¹H NMR (DMSO-d₆,400 MHz): 9.07 (1H, s), 7.84 (1H, s), 7.71 (1H, m), 7.25 (1H, s), 7.10(1H, m), 6.80-6.78 (1H, m), 5.96 (1H, m), 3.80 (3H, s), 3.35 (2H, m),2.55 (3H, s), 2.36 (2H, bm), 2.02 (2H, bm), 1.76 (2H, bm), 1.64 (2H,bm), 1.16 (3H, t). 137 A (55%)

2-amino-8- cyclopentyl-6-(4- hydroxy-3- methoxyphenyl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 367 (M + H)⁺ ¹H NMR (DMSO-d₆,400 MHz): 9.07 (1H, s), 7.83 (1H, s), 7.65-7.57 (1H, m), 7.24 (1H, s),7.08 (1H, m), 6.80- 6.78 (1H, m), 6.02-5.97 (1H, m), 3.80 (3H, s), 2.55(3H, s), 2.24 (2H, bm), 2.02 (2H, bm), 1.76 (2H, bm), 1.59 (2H, bm). 138A (45%)

6-(6-chloropyridin-3- yl)-8-cyclopentyl-4- methyl-2- (methylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one 370 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.71(1H, s), 8.20 (1H, m), 8.15 (1H, s), 7.82 (1H, m), 7.57 (1H, m), 5.99(1H, m), 2.58 (3H, s), 2.51 (3H, s), 2.37 (2H, bm), 2.00 (2H, bm), 1.79(2H, bm), 1.63 (2H, bm). 139 A (61%)

8-cyclopentyl-2- (ethylamino)-6-(6- methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 380 (M + H)⁺ ¹H NMR (DMSO-d₆,400 MHz): 8.43 (1H, s), 8.02 (1H, m), 7.99 (1H, s), 7.80 (1H, bs),6.86-6.84 (1H, m), 5.96 (1H, m), 3.88 (3H, s), 3.34 (2H, m), 2.55 (3H,s), 2.36 (2H, bm), 1.97 (2H, bm), 1.78 (2H, bm), 1.64 (2H, bm), 1.16(3H, t). 140 A (71%)

8-cyclopentyl-6-(6- methoxypyridin-3-yl)- 4-methyl-2-(methylamino)pyrido [2,3-d]pyrimidin- 7(8H)-one 366 (M + H)⁺ ¹H NMR(DMSO-d₆, 400 MHz): 8.43 (1H, s), 8.02 (1H, m), 7.99 (1H, s), 7.17 (2H,bs), 6.86-6.84 (1H, m), 6.02- 5.98 (1H, m), 3.88 (3H, s), 2.86 (3H, s),2.56 (3H, s), 2.24-2.23 (2H, bm), 2.02 (2H, bm), 1.76 (2H, bm), 1.59(2H, bm). 141 A

ethyl 3-[8-cyclopentyl- 4-methyl-2- (methylamino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-6- yl]benzoate 284 (M + H)⁺ ¹H NMR(DMSO-d₆, 400 MHz): δ ppm 1.34 (q, J = 6.91 Hz, 3H), 1.57-1.68 (m, 2H),1.78 (d, J = 6.06 Hz, 2H), 1.99 (s, 2H), 2.35-2.43 (m, 1H), 2.56-2.59(m, 2H), 2.89 (d, J = 4.55 Hz, 3H), 4.35 (q, J = 7.07 Hz, 2H), 5.94-6.05(m, 1H), 7.56 (t, J = 7.71 Hz, 1H), 7.73 (s, 1H), 7.88-7.94 (m, 2H),7.99-8.03 (m, 1H), 8.26 (s, 1H). 142 A (73%)

8-cyclopentyl-2- (ethylamino)-6-(3- methoxyphenyl)-4- methylpyrido[2,3-d]pyrimidin- 7(8H)-one 379 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.03(1H, s), 7.41 (1H, m), 7.33-7.31 (4H, m), 7.03- 7.00 (1H, m), 6.11 (1H,m), 3.89 (3H, s), 3.34 (2H, m), 2.55 (3H, s), 2.34 (2H, bm), 2.14 (2H,bm), 1.87 (2H, bm), 1.69 (2H, bm), 1.17 (3H, m). 143 A (62%)

8-cyclopentyl-6-(3- methoxyphenyl)-4- methyl-2- (methylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one 365 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.03(1H, s), 7.41 (1H, m), 7.33-7.31 (4H, m), 7.03- 7.00 (1H, m), 6.11 (1H,m), 3.89 (3H, s), 2.86 (3H, s), 2.66 (3H, s), 2.34 (2H, bm), 2.14 (2H,bm), 1.87 (2H, bm), 1.69 (2H, bm). 144 A (45%)

8-cyclopentyl-2- (ethylamino)-6-(3- hydroxyphenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 351 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 9.36 (1H,s), 7.87 (1H, s), 7.20-7.15 (1H, m), 7.11 (1H, m), 7.05-7.03 (1H, s),6.74-6.71 (1H, m), 5.98 (1H, m), 3.36 (2H, m), 2.54 (3H, s), 2.37 (2H,m), 2.02 (2H, m), 1.76 (2H, m), 1.64 (2H, m), 1.16 (3H, m). 145 A (70%)

2-amino-8- cyclopentyl-6-(3- methoxyphenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 351 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.03 (1H,s), 7.41 (1H, m), 7.33-7.31 (4H, m), 7.03- 7.00 (1H, m), 6.11 (1H, m),3.89 (3H, s), 2.66 (3H, s), 2.34 (2H, bm), 2.14 (2H, bm), 1.87 (2H, bm),1.69 (2H, bm). 146 A (56%)

8-cyclopentyl-6-(3- hydroxyphenyl)-4- methyl-2- (methylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one 351 (M + H)⁺ ¹H NMR (DMSO-d₆, 400 MHz): 9.37(1H, s), 7.88 (1H, s), 7.69 (1H, m), 7.19 (1H, m), 7.17 (1H, s), 7.05(1H, d), 6.74-6.71 (1H, m), 6.04-5.99 (1H, m), 2.89 (3H, s), 2.54 (3H,s), 2.36 (2H, m), 2.02 (2H, m), 1.77-1.75 (2H, m), 1.60-1.58 (2H, m).154 F

2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-6-(1-methyl-1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 355 (400 MHz,DMSO-d6) δ ppm 1.23-1.35 (m, 2H) 1.42- 1.53 (m, 2H) 1.89-1.97 (m, 2H)2.56 (s, 3H) 2.72-2.84 (m, 2H) 3.49-3.60 (m, 1H) 3.85 (s, 3H) 4.62 (d, J= 4.29 Hz, 1H) 5.23-5.72 (m, 1H) 7.05 (s, 2H) 8.08 (d, J = 7.58 Hz, 2H)8.34 (s, 1H) 155 F

2-amino-8-[(1R,3S)-3- hydroxycyclopentyl]-6- (6-methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 368 (400 MHz, DMSO-d6) δppm 1.70-1.81 (m, 2H) 1.92- 2.03 (m, 2H) 2.24-2.36 (m, 2H) 2.57 (s, 3H)3.88 (s, 3H) 4.03-4.12 (m, 1H) 4.97 (d, J = 6.82 Hz, 1H) 5.98- 6.08 (m,1H) 6.86 (d, J = 8.59 Hz, 1H) 7.21 (s, 2H) 7.99- 8.02 (m, 1H) 8.03 (s,1H) 8.43 (d, J = 2.02 Hz, 1H) 156 F

2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 341 (400 MHz, DMSO-d6) δ ppm1.21-1.36 (m, 2H) 1.43- 1.53 (m, 2H) 1.89-1.98 (m, 2H) 2.56 (s, 3H)2.72-2.84 (m, 2H) 3.50-3.62 (m, 1H) 4.61 (d, J = 4.04 Hz, 1H) 5.23- 5.65(m, 1H) 7.03 (s, 2H) 8.11 (s, 1H) 8.13 (s, 1H) 8.34 (s, 1H) 12.85 (s,1H) 157 F

2-amino-6-bromo-8- (trans-4- hydroxycyclohexyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 354 (400 MHz, DMSO-d6) δ ppm 1.21-1.32 (m, 2H)1.43- 1.53 (m, 2H) 1.86-1.96 (m, 2H) 2.48 (s, 3H) 2.59-2.71 (m, 2H)3.46-3.57 (m, 1H) 4.62 (d, J = 3.03 Hz, 1H) 5.08- 5.76 (m, 1H) 7.26 (s,2H) 8.34 (s, 1H) 158 F

2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-6-(1H-pyrrolo[2,3-b]pyridin- 5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 391 (400MHz, DMSO-d6) δ ppm 1.24-1.35 (m, 2H) 1.48- 1.58 (m, 2H) 1.90-1.99 (m,2H) 2.56 (s, 3H) 2.74-2.85 (m, 2H) 3.48-3.60 (m, 1H) 4.61 (d, J = 4.29Hz, 1H) 5.25- 5.69 (m, 1H) 6.47 (dd, J = 3.54, 1.77 Hz, 1H) 7.12 (s, 2H)7.45-7.51 (m, 1H) 7.97 (s, 1H) 8.21 (d, J = 1.77 Hz, 1H) 8.44 (d, J =2.02 Hz, 1H) 11.66 (s, 1H) 159 F

2-amino-8-[(1R,3R)-3- hydroxycyclopentyl]-6- (6-methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 368 (400 MHz, DMSO-d6) δppm 1.54-1.63 (m, 1H) 1.63- 1.71 (m, 1H) 1.91-2.01 (m, 1H) 2.03-2.13 (m,1H) 2.21- 2.30 (m, 1H) 2.38-2.46 (m, 1H) 2.55 (s, 3H) 3.88 (s, 3H)4.40-4.46 (m, 1H) 4.53 (d, J = 3.28 Hz, 1H) 6.21- 6.30 (m, 1H) 6.85 (d,J = 8.59 Hz, 1H) 7.17 (s, 2H) 7.99 (s, 1H) 7.99-8.02 (m, 1H) 8.42 (d, J= 2.02 Hz, 1H) 160 F

2-amino-6-bromo-8- [(1R,3S)-3- hydroxycyclopentyl]-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 340 (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 2H)1.90- 2.01 (m, 2H) 2.18-2.28 (m, 2H) 2.49 (s, 3H) 4.01-4.12 (m, 1H) 4.89(d, J = 6.32 Hz, 1H) 5.93-6.03 (m, 1H) 7.30 (s, 2H) 8.39 (s, 1H) 161 F

2-amino-8-[(1R,3S)-3- hydroxycyclopentyl]-4- methyl-6-(1-methyl-1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 341 (400 MHz,DMSO-d6) δ ppm 1.71-1.81 (m, 2H) 1.93- 2.04 (m, 2H) 2.24-2.35 (m, 2H)2.58 (s, 3H) 3.87 (s, 3H) 4.04-4.14 (m, 1H) 5.03 (d, J = 6.82 Hz, 1H)6.00- 6.10 (m, 1H) 7.10 (s, 2H) 8.09 (s, 1H) 8.15 (s, 1H) 8.34 (s, 1H)162 F

2-amino-8-[(1R,3S)-3- hydroxycyclopentyl]-4- methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 327 (400 MHz, DMSO-d6) δ ppm1.71-1.81 (m, 2H) 1.94- 2.04 (m, 2H) 2.26-2.36 (m, 2H) 2.59 (s, 3H)4.05-4.14 (m, 1H) 5.04 (d, J = 6.82 Hz, 1H) 5.99-6.09 (m, 1H) 7.09 (s,2H) 8.15 (s, 1H) 8.16 (s, 1H) 8.35 (s, 1H) 12.88 (s, 1H) 163 F

2-amino-8-[(1R,3S)-3- hydroxycyclopentyl]-4- methyl-6-(1H-pyrrolo[2,3-b]pyridin-5- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 377 (400MHz, DMSO-d6) δ ppm 1.71-1.83 (m, 2H) 1.94- 2.05 (m, 2H) 2.26-2.38 (m,2H) 2.59 (s, 3H) 4.05-4.13 (m, 1H) 5.01 (d, J = 7.07 Hz, 1H) 6.02-6.11(m, 1H) 6.49 (dd, J = 3.41, 1.89 Hz, 1H) 7.18 (s, 2H) 7.45-7.53 (m, 1H)8.03 (s, 1H) 8.22 (d, J = 1.77 Hz, 1H) 8.46 (d, J = 2.27 Hz, 1H) 11.68(s, 1H) 164 F

2-amino-8-[(1R,3R)-3- hydroxycyclopentyl]-4- methyl-6-(1-methyl-1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 341 (400 MHz,DMSO-d6) δ ppm 1.56-1.62 (m, 1H) 1.62- 1.70 (m, 1H) 1.91-2.01 (m, 1H)2.03-2.13 (m, 1H) 2.24- 2.34 (m, 1H) 2.38-2.46 (m, 1H) 2.57 (s, 3H) 3.86(s, 3H) 4.43-4.51 (m, 1H) 4.54 (d, J = 3.28 Hz, 1H) 6.24- 6.33 (m, 1H)7.07 (s, 2H) 8.08 (s, 1H) 8.11 (s, 1H) 8.33 (s, 1H) 165 F

2-amino-8-[(1R,3R)-3- hydroxycyclopentyl]-4- methyl-6-(1H-pyrrolo[2,3-b]pyridin-5- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 377 (400MHz, DMSO-d6) δ ppm 1.55-1.64 (m, 1H) 1.65- 1.73 (m, 1H) 1.93-2.03 (m,1H) 2.06-2.16 (m, 1H) 2.22- 2.33 (m, 1H) 2.40-2.47 (m, 1H) 2.57 (s, 3H)4.41- 4.47 (m, 1H) 4.53 (d, J = 3.03 Hz, 1H) 6.24-6.34 (m, 1H) 6.48 (dd,J = 3.28, 1.77 Hz, 1H) 7.14 (s, 2H) 7.46-7.49 (m, 1H) 7.99 (s, 1H) 8.21(d, J = 2.02 Hz, 1H) 8.45 (d, J = 2.02 Hz, 1H) 11.66 (s, 1H) 166 F

2-amino-8-[(1R,3R)-3- hydroxycyclopentyl]-4- methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 327 (400 MHz, DMSO-d6) δ ppm1.56-1.63 (m, 1H) 1.63- 1.69 (m, 1H) 1.90-2.00 (m, 1H) 2.05-2.14 (m, 1H)2.25- 2.34 (m, 1H) 2.40-2.46 (m, 1H) 2.58 (s, 3H) 4.43- 4.50 (m, 1H)4.53 (d, J = 3.03 Hz, 1H) 6.23-6.32 (m, 1H) 7.05 (s, 2H) 8.12 (s, 1H)8.13 (s, 1H) 8.34 (s, 1H) 12.86 (s, 1H) 167 F

2-amino-6-bromo-8- (2-hydroxy-2- methylpropyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 328 (400 MHz, DMSO-d6) δ ppm 1.09 (s, 6H) 2.52 (s,3H) 4.41 (s, 2H) 4.65 (s, 1H) 7.34 (s, 2H) 8.41 (s, 1H) 168 F

2-amino-6-bromo-8- (cis-4- hydroxycyclohexyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one (400 MHz, DMSO-d6) δ ppm 1.20-1.27 (m, 2H) 1.43-1.55 (m, 2H) 1.74-1.83 (m, 2H) 2.49 (s, 3H) 2.88-3.00 (m, 2H) 3.83-3.90(m, 1H) 4.31 (d, J = 2.78 Hz, 1H) 5.39- 5.50 (m, 1H) 7.16-7.27 (m, 2H)8.33 (s, 1H) 169 F

2-amino-8-(2-hydroxy- 2-methylpropyl)-6-(6- methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 356 (400 MHz, DMSO-d6) δ ppm1.12 (s, 6H) 2.58 (s, 3H) 3.88 (s, 3H) 4.46 (s, 2H) 4.79 (s, 1H) 6.87(d, J = 8.59 Hz, 1H) 7.27 (s, 2H) 8.02 (dd, J = 8.59, 2.53 Hz, 1H) 8.07(s, 1H) 8.47 (d, J = 2.27 Hz, 1H) 170 F

2-amino-6-(4- fluorophenyl)-8-(2- hydroxy-2- methylpropyl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 343 (400 MHz, DMSO-d₆) δ ppm1.13 (s, 6H) 2.58 (s, 3H) 4.46 (s, 2H) 4.81 (s, 1H) 7.20-7.27 (m, 2H)7.27 (s, 2H) 7.70-7.77 (m, 2H) 8.02 (s, 1H) 171 F

2-amino-8-(cis-4- hydroxycyclohexyl)-4- methyl-6-(1H-pyrrolo[2,3-b]pyridin-6- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 391 (400MHz, DMSO-d₆) δ ppm 1.23-1.34 (m, 2H) 1.46- 1.57 (m, 2H) 1.76-1.86 (m,2H) 2.57 (s, 3H) 3.00-3.12 (m, 2H) 3.85-3.95 (m, 1H) 4.30 (d, J = 2.78Hz, 1H) 5.43- 5.55 (m, 1H) 6.47 (dd, J = 3.28, 1.77 Hz, 1H) 7.07 (s, 2H)7.43-7.53 (m, 1H) 7.97 (s, 1H) 8.22 (d, J = 1.77 Hz, 1 H) 8.46 (d, J =2.02 Hz, 1H) 11.66 (s, 1H) 172 F

2-amino-8-(2-hydroxy- 2-methylpropyl)-4- methyl-6-(1H-pyrrolo[2,3-b]pyridin-5- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 365 (400MHz, DMSO-d6) δ ppm 1.15H) 2.60 (s, 3H) 4.49 (s, 2H) 4.85 (s, 1H) 6.49(dd, J = 3.41, 1.89 Hz, 1H) 7.24 (s, 2H) 7.46-7.51 (m, 1H) 8.08 (s, 1H)8.24 (d, J = 1.77 Hz, 1H) 8.49 (d, J = 2.02 Hz, 1H) 11.69 (s, 1H) 173 F

2-amino-8-(2-hydroxy- 2-methylpropyl)-4- methyl-6-quinolin-3-ylpyrido[2,3- d]pyrimidin-7(8H)-one 376 (400 MHz, DMSO-d6) δ ppm 1.16(s, 6H) 2.63 (s, 3H) 4.50 (s, 2H) 4.81 (s, 1H) 7.36 (s, 2H) 7.61-7.68(m, 1H) 7.77 (ddd, J = 8.34, 6.95, 1.39 Hz, 1H) 8.00-8.07 (m, 2H) 8.32(s, 1H) 8.67 (d, J = 2.27 Hz, 1H) 9.20 (d, J = 2.02 Hz, 1H) 174 F

2-amino-8-(cis-4- hydroxycyclohexyl)-6- (6-methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 382 (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.58 (m, 2H) 1.63-1.74 (m, 2H) 1.89- 1.96 (m, 2H)1.96-2.00 (m, 1H) 2.60 (s, 3H) 3.01-3.13 (m, 2H) 3.97 (s, 3H) 4.06- 4.15(m, 1H) 5.21 (s, 2H) 5.46-5.58 (m, 1H) 6.80 (d, J = 8.59 Hz, 1H) 7.74(s, 1H) 7.98 (dd, J = 8.59, 2.53 Hz, 1H) 8.31 (d, J = 2.27 Hz, 1H) 175 F

2-amino-6-(6- methoxypyridin-3-yl)-4- methyl-8-(4- oxocyclohexyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 380 400 MHz, DMSO-d6) δ ppm 1.84-1.93 (m,2H) 2.34- 2.42 (m, 2H) 2.51-2.55 (m, 2H) 2.56 (s, 3H) 2.99-3.10 (m, 2H)3.88 (s, 3H) 5.86- 5.98 (m, 1H) 6.85 (d, J = 8.59 Hz, 1H) 7.21 (s, 2H)7.99- 8.04 (m, 2H) 8.45 (d, J = 2.27 Hz, 1H) 176 F

2-amino-4-methyl-8-(4- oxocyclohexyl)-6-(1H- pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 338 (400 MHz, DMSO-d6) δ ppm 1.82-1.92 (m, 2H)2.35- 2.42 (m, 2H) 2.51-2.56 (m, 2H) 2.58 (s, 3H) 3.02-3.14 (m, 2H)5.90-6.01 (m, 1H) 7.08 (s, 2H) 8.15 (s, 1H) 8.19 (s, 1H) 8.34 (s, 1H)12.87 (s, 1H) 177 F

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)-8- (cis-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 399 (400MHz, DMSO-d6) δ ppm 1.20-1.29 (m, 2H) 1.45- 1.56 (m, 2H) 1.75-1.84 (m,2H) 2.56 (s, 3H) 2.97-3.08 (m, 2H) 3.84-3.90 (m, 1H) 3.98 (s, 3H) 4.30(d, J = 2.78 Hz, 1H) 5.40-5.52 (m, 1H) 7.10-7.21 (m, 2H) 8.01 (dd, J =12.25, 1.89 Hz, 1 178 F

2-amino-6-bromo-8- (trans-4- methoxycyclohexyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 367 (400 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2H)1.49- 1.59 (m, 2H) 2.06-2.15 (m, 2H) 2.49 (s, 3H) 2.61-2.73 (m, 2H)3.17-3.26 (m, 1H) 3.27 (s, 3H) 5.15-5.67 (m, 1H) 7.26 (s, 2H) 8.34 (s,1H) 180 F

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)-8- (trans-4-methoxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 413 (400MHz, DMSO-d6) δ ppm 1.16-1.28 (m, 2H) 1.51- 1.61 (m, 2H) 2.07-2.16 (m,2H) 2.56 (s, 3H) 2.71-2.82 (m, 2H) 3.27 (s, 3H) 3.30- 3.32 (m, 1H) 3.98(s, 3H) 5.07-5.75 (m, 1H) 7.22 (s, 2H) 8.01 (dd, J = 12.25, 1.89 Hz, 1H)8.07 (s, 1H) 8 181 F

2-amino-6-[6- (dimethylamino)pyridin- 3-yl]-8-(cis-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 394 (400MHz, DMSO-d6) δ ppm 1.20-1.29 (m, 2H) 1.45- 1.55 (m, 2H) 1.75-1.84 (m,2H) 2.54 (s, 3H) 3.05 (s, 6H) 3.85-3.91 (m, 1H) 4.30 (d, J = 2.78 Hz,1H) 5.40- 5.51 (m, 1H) 6.65 (d, J = 8.84 Hz, 1H) 7.02 (s, 2H) 7.83- 7.87(m, 2H) 8.38 (d, J = 2 182 F

2-amino-6-[6- (dimethylamino)pyridin- 3-yl]-8-(trans-4-methoxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 409 (400MHz, DMSO-d6) δ ppm 1.15-1.27 (m, 2H) 1.51- 1.61 (m, 2H) 2.07-2.16 (m,2H) 2.53 (s, 3H) 2.73-2.84 (m, 2H) 3.05 (s, 6H) 3.27 (s, 3H) 3.30-3.32(m, 1H) 5.02- 5.65 (m, 1H) 6.65 (d, J = 9.09 Hz, 1H) 7.09 (s, 2H) 7.84(dd, J = 8.84, 2.27H 183 F

2-amino-8-(trans-4- methoxycyclohexyl)-4- methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 354 (400 MHz, DMSO-d6) δ ppm1.17-1.29 (m, 2H) 1.50- 1.59 (m, 2H) 2.08-2.16 (m, 2H) 2.57 (s, 3H)2.75-2.87 (m, 2H) 3.28 (s, 3H) 3.30- 3.33 (m, 1H) 5.17-5.73 (m, 1H) 7.05(s, 2H) 8.11 (s, 1H) 8.14 (s, 1H) 8.34 (s, 1H) 12.86 (s, 1H) 184 F

2-amino-6-bromo-4- methyl-8-(4- oxocyclohexyl)pyrido [2,3-d]pyrimidin-7(8H)-one 351 (400 MHz, CHLOROFORM- d) δ ppm 1.63-1.74 (m, 2H) 1.92-2.04(m, 2H) 2.48- 2.57 (m, 2H) 2.59 (s, 3H 3.04-3.15 (m, 2H) 5.33 (s, 2H)5.91-6.03 (m, 1H) 8.13 (s, 1H 185 F

2-amino-8-(4-hydroxy- 4-methylcyclohexyl)-4- methyl-6-(1H-pyrazol-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 355 (400 MHz, DMSO-d6) δ ppm 1.15(s, 3H) 1.20-1.30 (m, 2H) 1.36-1.47 (m, 2H) 1.63- 1.72 (m, 2H) 2.57 (s,3H) 2.98-3.10 (m, 2 H)4.05 (s, 1H) 5.40-5.52 (m, 1H) 6.98 (s, 2H) 8.10(s, 1H) 8.16 (s, 1H) 8.33 (s, 1H) 12.86 (s, 1H) 187 F

2-amino-8-(trans-4- methoxycyclohexyl)-4- methyl-6-(1H-pyrazol-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 355 (400 MHz, DMSO-d6) δ ppm1.17-1.29 (m, 2H) 1.51- 1.61 (m, 2H) 2.08-2.17 (m, 2H) 2.56 (s, 3H)2.76-2.87 (m, 2H) 3.28 (s, 3H) 3.28- 3.31 (m, 1H) 5.16-5.83 (m, 1H) 6.93(s, 1H) 7.14-7.26 (m, 2H) 7.40-7.90 (m, 1H) 8.35 (s, 1H) 12.62-13.24 (m,1H) 188 F

2-amino-8-(trans-4- hydroxycyclohexyl)-6- (6-isopropoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 410 (400 MHz, DMSO-d6) δppm 1.08-1.17 (m, 8H) 1.34 (d, J = 10.86 Hz, 2H) 1.76 (d, J = 10.11 Hz,2H) 2.38 (s, 3H) 2.50-2.61 (m, 2H) 3.37 (bs, 1H) 4.45 (bs, 1H) 5.11 (dt,J = 12.38, 6.19 Hz, 1H) 6.59 (d, J = 8.84 Hz, 1H) 6.99 (s, 2H) 7.76-7.84(m, 2H) 8.22 (d, J = 2.02 Hz, 1H) 189 F

2-amino-6-(6- ethoxypyridin-3-yl)-8- (trans-4- hydroxycyclohexyl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 396 (400 MHz, DMSO-d6) δ ppm1.22-1.31 (m, 2H) 1.34 (t, J = 7.07 Hz, 3H) 1.45-1.50 (m, 2H) 1.90-1.95(m, 2H) 2.55 (s, 3H) 2.70-2.79 (m, 2H) 3.54 (s, 1H) 4.33 (q, J = 6.99Hz, 2H) 4.62 (d, J = 4.29 Hz, 1H) 6.81 (d, J = 8.59 Hz, 1H) 7.16 (s, 2H)7.95-8.01 (m, 2H) 8.40 (d, J = 2.27 Hz, 1H) 190 F

5-[2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6- yl]pyridine-2- carbonitrile 377 (400MHz, DMSO-d6) δ ppm 1.22-1.34 (m, 2H) 1.50- 1.53 (m, 2H) 1.93 (d, J =9.60 Hz, 2H) 2.57 (s, 3H) 2.71- 2.83 (m, 2H) 3.50 (bs, 1H) 4.62 (d, J =4.04 Hz, 1H) 7.36 (s, 2H) 8.07 (d, J = 8.08 Hz, 1H) 8.24 (s, 1H) 8.37(dd, J = 8.08, 2.27 Hz, 1H) 9.06 (s, 1H) 191 F

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)-8- (trans-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 399 (400MHz, DMSO-d6) δ ppm 1.18-1.27 (m, 2H) 1.52- 1.55 (m, 2H) 1.90-1.95 (m,2H) 2.53 (s, 3H) 2.76 (bs, 2H) 3.54 (bs, 1H) 3.98 (s, 3H) 4.62 (d, J =4.29 Hz, 1H) 7.22 (s, 2H) 8.01 (dd, J = 12.25, 1.89 Hz, 1H) 8.06 (s, 1H)8.30 (d, J = 2.02 Hz, 1H) 194 F

2-amino-6-[6- (dimethylamino)pyridin- 3-yl]-8-(trans-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 395 (400MHz, DMSO-d6) δ ppm 1.23-1.34 (m, 2H) 1.48 (d, J = 1.01 Hz, 2H) 1.91 (m,2H) 2.51 (s, 3H) 2.68-2.78 (m, 2H) 3.03 (s, 6H) 3.53 (s, 1H) 4.61 (s,1H) 5.38 (s, 1H) 6.65 (d, J = 8.84 Hz, 1H) 7.08 (s, 2H) 7.80-7.88 (m,2H) 8.36 (d, J = 2.27 Hz, 1H) 195 Similar to Exam- ple 78

2-amino-6-(6- methoxypyridin-3-yl)-4- methyl-8-(pyrrolidin-1-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 353 (400 MHz, MeOD) δ ppm 2.03-2.18(m, 4H) 2.64 (s, 3H) 3.36-3.46 (m, 4H) 3.96 (s, 3H) 6.86 (d, J = 8.59Hz, 1H) 7.97-8.03 (m, 2H) 8.42 (d, J = 2.53 Hz, 1H) 196 Similar to Exam-ple 78

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)- 4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 371 (400 MHz, MeOD) δ ppm2.05-2.12 (m, 4H) 2.62 (s, 3H) 3.35-3.43 (m, 4H) 4.02 (s, 3H) 7.85 (dd,J = 11.62, 2.02 Hz, 1H) 8.02 (s, 1H) 8.21 (d, J = 2.02 Hz, 1H) 197 F

2-amino-4-methyl-6- (1 H-pyrazol-4-yl)-8- (2,2,2- trifluoroethyl)pyrido[2,3-d]pyrididin- 7(8H)-one 325 (400 MHz, DMSO-d₆) δ ppm 2.62 (s, 3H)5.19 (q, J = 9.01 Hz, 2H) 7.25 (s, 2H) 8.18 (s, 1H) 8.25 (s, 1H) 8.38(s, 1H) 12.93 (s, 1H) 198 F

2-amino-6-(6- methoxypyridin-3-yl)- 4-methyl-8-(2,2,2-trifluoroethyl)pyrido [2,3-d]pyrimidin- 7(8H)-one 366 (400 MHz, DMSO-d₆)δ ppm 2.60 (s, 3H) 3.89 (s, 3H) 5.16 (q, J = 8.93 Hz, 2H) 6.89 (d, J =8.84 Hz, 1H) 7.39 (s, 2H) 8.03 (dd, J = 8.59, 2.53 Hz, 1H) 8.13 (s, 1H)8.49 (d, J = 2.27 Hz, 1H) 199 F

2-amino-4-methyl-6- (1H-pyrazol-4-yl)-8- (tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 327 (400 MHz, DMSO-d6) δ ppm:12.86 (1H, s), 8.35 (1H, s), 8.15 (1H, s), 8.13 (1H, s), 7.07 (2H, s),5.72 (1H, s), 4.00 (2H, dd, J = 11.24, 3.92 Hz), 3.35-3.48 (2H, m),2.89- 3.10 (2H, m), 2.58 (3H, s), 1.46 (2H, dd, J = 11.62, 2.53 Hz) 200F

2-amino-6-(6- methoxypyridin-3-yl)- 4-methyl-8- (tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 368 (400 MHz, DMSO-d6) δ ppm:8.43 (1H, d, J = 2.53 Hz), 7.92-8.06 (2H, m), 7.19 (2H, s), 6.85 (1H, d,J = 8.59 Hz), 5.58-5.84 (1H, m), 3.99 (2H, dd, J 11.24, 4.17 Hz), 3.88(3H, s), 3.36-3.47 (2H, m), 2.86-3.09 (2H, m), 2.55 (3H, s), 1.48 (2H,dd, J = 11.24, 2.40 Hz) 201 F

2-amino-4-methyl-6- (1H-pyrrolo[2,3- b]pyridin-5-yl)-8-(tetrahydro-2H-pyran- 4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 377 (400MHz, DMSO-d6) δ ppm: 11.66 (1H, s), 8.46 (1H, s), 8.22 (1H s), 8.00 (1H,s), 7.48 (1H, s), 7.15 (2H, s), 6.48 (1H, s), 5.73 (1H, t, J = 11.12Hz), 4.00 (2H, d, J = 7.83 Hz), 3.41 (2H, t, J = 11.75 Hz), 2.89-3.10(2H, m), 2.57 (3H, s), 1.50 (2H, d, J = 11.12 Hz) 202 F

2-amino-6-bromo-4- methyl-8- (tetrahydrofuran-3- yl)pyrido[2,3-d]pyrimidin-7(8H)-one 325 (400 MHz, DMSO-d6) δ ppm: 8.38 (1H, s), 7.32(2H, s), 6.08-6.32 (1H, m), 4.20 (1H, q, J = 7.58 Hz), 3.75-3.97 (3H,m), 3.36 (3H, s), 2.26- 2.41 (1H, m), 1.95-2.13 (1H, m) 203 F

2-amino-4-methyl-6- (1H-pyrazol-4-yl)-8- (tetrahydrofuran-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 313 (400 MHz, DMS0-d6) δ ppm: 12.87(1H, s), 8.35 (1H, s), 8.15 (2H, s), 7.10 (2H, s), 6.17-6.34 (1H, m),4.28 (1H, q, J = 7.58 Hz), 3.80-4.04 (3H, m), 2.59 (3H, s), 2.35- 2.47(1H, m), 1.97-2.15 (1H, m) 204 F

2-amino-6-(6- methoxypyridin-3-yl)- 4-methyl-8- (tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 354 (400 MHz, CDCl₃) δ ppm: 8.32(1H, d, J = 2.27 Hz), 7.97 (1H, dd, J = 8.59, 2.53 Hz), 7.77 (1H, s),6.82 (1H, d, J = 8.59 Hz), 6.24-6.43 (1H, m), 5.26 (2H, s), 4.39 (1H, q,J = 7.66 Hz), 4.16 (1H, t, J = 7.71 Hz), 4.00-4.10 (2H, m), 3.98 (3H,s), 2.62 (3H, s), 2.48-2.59 (1H, m), 2.13-2.29 (1H, m) 205 F

2-amino-8-cyclobutyl- 4-methyl-6-(1H- pyrazol-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one 297 (400 MHz, DMSO-d6) δ ppm: 12.87 (1H, s), 8.25(2H, br. s.), 8.11 (1H, s), 7.07 (2H, s), 5.88-6.06 (1H, m), 3.04-3.23(2H, m), 2.57 (3H, s), 2.11- 2.28 (2H, m), 1.89-2.04 (1H, m), 1.68-1.84(1H, m) 206 F

2-amino-8-cyclobutyl- 6-(6-methoxypyridin-3- yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 338 (400 MHz, DMSO-d6) δ ppm: 8.43 (1H, d, J =2.27 Hz), 8.01 (1H, dd, J = 8.59, 2.53 Hz), 7.98 (1H, s), 7.18 (2H, s),6.85 (1H, d, J = 8.59 Hz), 5.84-6.00 (1H, m), 3.88 (3H, s), 3.02-3.19(2H, m), 2.55 (3H, s), 2.13-2.29 (2H, m), 1.87-2.01 (1H, m), 1.66-1.84(1H, m) 207 F

2-amino-8-cyclobutyl- 4-methyl-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 347 (400 MHz, DMSO-d6) δ ppm: 11.67(s, 1H) 8.46 (1H, d, J = 2.02 Hz), 8.22 (1H, d, J = 2.02 Hz), 7.99 (1H,s), 7.45- 7.51 (1H, m), 7.15 (2H, s), 6.48 (1H, dd, J = 3.28, 1.77 Hz),5.87-6.04 (1H, m), 3.05- 3.22 (2H, m), 2.56 (3H, s), 2.16-2.30 (2H, m),1.88-2.04 (1H, m), 1.67-1.83 (1H, m) 208 E

2-amino-8-isopropyl-4- methyl-6-(1H-pyrazol- 4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 285 (400 MHz, DMSO-d6) δ ppm: 12.86 (1H, br. s.),8.35 (1H, br. s.), 8.12-8.24 (1H, m), 8.11 (1H, s), 7.04 (2H, s), 5.86(1H, br. s.), 2.57 (3H, s), 1.53 (6H, d, J = 7.07 Hz) 209 E

2-amino-8-isopropyl-6- (6-methoxypyridin-3- yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 326 (400 MHz, DMSO-d6) δ ppm: 8.43 (1H, d, J =2.27 Hz), 8.01 (1H, dd, J = 8.59, 2.53 Hz), 7.98 (1H, s), 7.17 (2H, s),6.85 (1H, d, J = 8.59 Hz), 5.84 (1H, br. s.), 3.88 (3H, s), 2.55 (3H,s), 1.53 (6H, d, J = 7.07 Hz) 210 E

2-amino-8-isopropyl-4- methyl-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 335 (400 MHz, DMSO-d6) δ ppm: 11.67(1H, br. s.), 8.46 (1H, d, J = 2.02 Hz), 8.22 (1H, d, J = 2.02 Hz), 7.98(1H, s), 7.48 (1H, t, J = 2.78 Hz), 7.14 (2H, s), 6.48 (1H, dd, J =3.16, 1.89 Hz), 5.87 (1H, br. s.), 2.57 (3H, s), 1.55 (6H, d, J = 6.82Hz) 211 F

2-amino-8- cyclopropyl-4-methyl- 6-(1H-pyrazol-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one 283 (400 MHz, DMSO-d6) δ ppm: 12.85 (1H, s), 8.33(1H, s), 8.14 (1H, s), 8.10 (1H, s), 6.98 (2H, s), 2.79-2.94 (1H, m),2.55 (3H, s), 1.09-1.25 (2H, m), 0.71-0.86 (2H, m) 212 F

2-amino-8- cyclopropyl-6-(6- methoxypyridin-3-yl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 324 (400 MHz, DMSO-d6) δ ppm: 8.44 (1H, d, J =2.53 Hz), 8.00 (1H, dd, J = 8.59, 2.53 Hz), 7.97 (1H, s), 7.10 (2H, s),6.85 (1H, d, J = 8.59 Hz), 3.88 (3H, s), 2.80-2.92 (1H, m), 2.54 (3H,s), 1.11-1.18 (2H, m), 0.74-0.83 (2H, m) 213 F

2-amino-8-cyclopropyl- 4-methyl-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 333 (400 MHz, DMSO-d6) δ ppm:11.67 (1H, s), 8.46 (1H, d, J = 2.02 Hz), 8.21 (1H, d, J = 1.77 Hz),7.98 (1H, s), 7.42- 7.53 (1H, m), 7.06 (2H, s), 6.48 (1H, dd, J = 3.41,1.89 Hz), 2.80-2.95 (1H, m), 2.55 (3H, s), 1.17 (2H, q, J = 7.16 Hz),0.75-0.88 (2H, m) 214 E

6-bromo-4-methyl-2- (methylamino)-8- ((tetrahydrofuran-3-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 353 (400 MHz, CDCl₃) δ ppm:8.11 (1H, s), 5.54 (1H, br. s.), 4.33-4.68 (2H, m), 3.91-4.03 (1H, m),3.72-3.87 (2H, m), 3.68 (1H, dd, J = 8.59, 6.06 Hz), 3.06 (3H, d, J =4.80 Hz), 2.79-2.97 (1H, m), 2.54 (3H, s), 1.90-2.03 (1H, m), 1.74-1.88(1H, m) 215 E

4-methyl-2- (methylamino)-6-(1H- pyrazol-4-yl)-8- ((tetrahydrofuran-3-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 341 (400 MHz, DMSO-d6) δppm: 12.88 (1H, s), 8.38 (1H, s), 8.19 (1H, s), 8.18 (1H, s), 7.64 (1H,d, J = 4.80 Hz), 4.24-4.55 (2H, m), 3.76-.89 (1H, m), 3.51-3.70 (3H, m),2.87 (3H, d, J = 4.80 Hz), 2.74-2.84 (1H, m), 2.59 (3H, s), 1.79-1.96(1H, m), 1.59- 1.77 (1H, m) 216 E

6-(6-methoxypyridin-3- yl)-4-methyl-2- (methylamino)-8-((tetrahydrofuran-3- yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 382(400 MHz, DMSO-d6) δ ppm: 8.48 (1H, d, J = 1.77 Hz), 8.06 (1H, s), 8.03(1H, d, J = 2.27 Hz), 7.50-7.82 (1H, m), 6.86 (1H, d, J = 8.59 Hz),4.23-4.55 (2H, m), 3.88 (3H, s), 3.76-3.85 (1H, m), 3.50- 3.69 (3H, m),2.88 (3H, d, J = 4.80 Hz), 2.72-2.84 (1H, m), 2.57 (3H, s), 1.79-1.95(1H, m), 1.59-1.78 (1H, m) 217 E

4-methyl-2- (methylamino)-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)-8-((tetrahydrofuran- 3-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one391 (400 MHz, DMSO-d6) δ ppm: 11.67 (1H, s), 8.50 (1H, s), 8.25 (1H, s),8.06 (1H, s), 7.51-7.78 (1H, m), 7.44-7.50 (1H, m), 6.48 (1H, dd, J =3.28, 1.77 Hz), 4.31-4.56 (2H, m), 3.77-3.90 (1H, m), 3.52-3.73 (3H, m),2.89 (3H, d, J = 4.80 Hz), 2.74-2.86 (1H, m), 2.58 (3H, s), 1.81- 1.96(1H, m), 1.62-1.80 (1H, m) 218 E

2-amino-6-bromo-4- methyl-8- ((tetrahydrofuran-3- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 339 (400 MHz, DMSO-d6) δ ppm: 8.40 (1H, s), 7.31(2H, s), 4.39 (1H, dd, J = 12.63, 7.83 Hz), 4.23 (1H, dd, J = 12.63,7.07 Hz), 3.82 (1H, dt, J = 7.89, 5.68 Hz), 3.57-3.68 (2H, m), 3.51 (1H,dd, J = 8.46, 5.68 Hz), 3.3 (3H, s), 2.67-2.82 (1H, m), 1.76-1.89 (1H,m), 1.54-1.68 (1H, m) 219 E

2-amino-4-methyl-6- (1H-pyrazol-4-yl)-8- ((tetrahydrofuran-3-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 327 (400 MHz, DMSO-d6) δppm: 12.87 (1H, s), 8.37 (1H, s), 8.18 (2H, s), 7.07 (2H, s), 4.45 (1H,dd, J = 12.63, 7.83 Hz), 4.28 (1H, dd, J = 12.63, 7.07 Hz), 3.84 (1H, dtJ = 7.83, 5.81 Hz), 3.58-3.70 (2H, m), 3.55 (1H, dd, J = 8.34, 5.81 Hz),2.72-2.85 (1H, m), 2.59 (3H, s), 1.77- 1.90 (1H, m), 1.58-1.72 (1H, m)220 E

2-amino-6-(6- methoxypyridin-3-yl)- 4-methyl-8- ((tetrahydrofuran-3-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 368 (400 MHz, DMSO-d6) δppm: 8.47 (1 H, d, J = 2.27 Hz), 8.00-8.08 (2H, m), 7.21 (2H, s), 6.86(1H, d, J = 8.59 Hz), 4.43 (1H, dd, J = 12.51, 7.71 Hz), 4.26 (1H, dd, J= 12.63, 7.07 Hz), 3.88 (3H, s), 3.78- 3.86 (1H, m), 3.58-3.70 (2H, m),3.55 (1H, dd, J = 8.46, 5.68 Hz), 2.71-2.85 (1H, m), 2.57 (3H, s),1.78-1.91 (1H, m), 1.59-1.73 (1H, m) 221 E

2-amino-4-methyl-6- (1H-pyrrolo[2,3- b]pyridin-5-yl)-8-((tetrahydrofuran-3- yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 377(400 MHz, DMSO-d6) δ ppm: 11.68 (1H, s), 8.49 (1H, d, J = 2.02 Hz),8.25(1H, d, J = 1.77 Hz), 8.05 (1H, s), 7.45- 7.52 (1H, m), 7.17 (2H,s), 6.48 (1H, dd, J = 3.41, 1.89 Hz), 4.46 (1H, dd, J = 12.51, 7.71 Hz),4.29 (1H, dd J = 12.63, 6.82 Hz), 3.79-3.90 (1H, m), 3.52-3.72 (3H, m),2.73-2.88 (1H, m), 2.59 (3H, s), 1.80-1.92 (1H, m), 1.62- 1.74 (1H, m).222 E

2-amino-6-bromo-4- methyl-8- ((tetrahydrofuran-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 339 (400 MHz, DMSO-d6) δ ppm: 8.39 (1H, s), 7.30(2H, s), 4.47 (1H, dd, J = 12.38, 7.83 Hz), 4.24-4.37 (1H, m), 4.16 (1H,dd, J = 12.38, 5.56 Hz), 3.74-3.84 (1H, m), 3.55-3.65 (1H, m), 2.51 (3H,s), 1.73- 2.02 (3H, m), 1.60-1.70 (1H, m) 223 E

2-amino-4-methyl-6- (1H-pyrazol-4-yl)-8- ((tetrahydrofuran-2-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 327 (400 MHz, DMSO-d6) δppm: 12.87 (1H, br. s.), 8.35 (2H, br. s.), 8.17 (1H, s), 7.06 (2H, s),4.51 (1H, dd, J = 12.38, 7.58 Hz), 4.28-4.41 (1H, m), 4.23 (1H, dd, J =12.38, 6.06 Hz), 3.75-3.88 (1H, m), 3.53- 3.66 (1H, m), 2.58 (3H, s),1.89-2.06 (1H, m), 1.74-1.88 (2H, m), 1.60-1.74 (1H, m) 224 E

2-amino-6-(6- methoxypyridin-3-yl)- 4-methyl-8- ((tetrahydrofuran-2-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 368 (400 MHz, DMSO-d6) δppm: 8.47 (1H, d, J = 2.02 Hz), 7.98-8.08 (2H, m), 7.19 (2H, s), 6.86(1H, d, J = 8.59 Hz), 4.50 (1H, dd, J = 12.13, 7.58 Hz), 4.28-4.39 (1H,m), 4.20 (1H, dd, J = 12.25, 5.94 Hz), 3.89 (3H, s), 3.81 (1 H, td, J =7.77, 5.68 Hz), 3.53-3.66 (1H, m), 2.57 (3H, s), 1.91- 2.04 (1H, m),1.62-1.90 (3H, m) 225 E

2-amino-4-methyl-6- (1H-pyrrolo[2,3- b]pyridin-5-yl)-8-((tetrahydrofuran-2- yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one 377(400 MHz, DMSO-d6) δ ppm: 11.67 (1H, br. s.), 8.49 (1H, d, J = 2.02 Hz),8.24 (1H, d, J = 2.02 Hz), 8.05 (1H, s), 7.44-7.55 (1H, m), 7.15 (2H,br. s.), 6.49 (1H, dd, J = 3.41, 1.89 Hz), 4.52 (1H, dd, J = 12.38, 7.58Hz), 4.30-4.45 (1H, m), 4.23 (1H, dd, J = 12.38, 5.81 Hz), 3.76-3.91(1H, m), 3.54-3.68 (1H, m), 2.58 (3H, s), 1.62-2.10 (4H, m) 226 F

tert-butyl 3-(2-amino- 4-methyl-7-oxo-6-(1H- pyrazol-4- yl)pyrido[2,3-d]pyrimidin-8(7H)- yl)azetidine-1- carboxylate 398 (400 MHz, DMSO-d6) δppm: 12.90 (1H, s), 8.33 (1H, s), 8.16 (2H, s), 7.08 (2H, s), 5.51-5.69(1H, m), 4.30 (2H, t, J = 7.96 Hz), 4.22 (2H, t, J = 8.34 Hz), 2.58 (3H,s), 1.41 (9H, s) 227 F

tert-butyl 3-(2-amino- 6-(6-methoxypyridin-3- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl)azetidine-1- carboxylate 439 (400MHz, DMSO-d6) δ ppm: 8.45 (1H, s), 8.03 (1H, s), 8.01 (1H, s), 7.18 (2H,s), 6.86 (1 H, d, J = 8.34 Hz), 5.38-5.65 (1H, m), 4.12-4.38 (4H, m),3.88 (3H, s), 2.56 (3H, s), 1.39 (9H, s) 228 F

tert-butyl 3-(2-amino- 4-methyl-7-oxo-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)pyrido[2,3- d]pyrimidin-8(7H)- yl)azetidine-1- carboxylate 448 (400MHz, DMSO-d6) δ ppm: 11.69 (1H, s), 8.48 (1H, d, J = 2.02 Hz), 8.24 (1H,d, J = 2.02 Hz), 8.04 (1H, s), 7.44- 7.53 (1H, m), 7.17 (2H, s), 6.48(1H, dd, J = 3.28, 1.77 Hz), 5.47-5.63 (1H, m), 4.32 (2H, t, J = 7.71Hz), 4.23 (2H, t, J = 8.34 Hz), 2.58 (3H, s), 1.39 (9H, s). 229 A

2-amino-6-(5- aminopyrazin-2-yl)-8- cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 338 (400 MHz, DMSO-d6) δ ppm 1.54-1.66 (m, 2H)1.71- 1.83 (m, 2H) 1.98-2.11 (m, 2H) 2.26 (dd, J = 11.12, 7.58 Hz, 2H)2.55 (s, 3H) 5.94- 6.11 (m, 1H) 6.56 (s, 2H) 7.18 (s, 2H) 7.97 (d, J =1.52 Hz, 1H) 8.39 (s, 1H) 8.90 (d, J = 1.52 Hz, 1H) 230 A

2-amino-6-(6- aminopyrazin-2-yl)-8- cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 338 (400 MHz, DMSO-d6) δ ppm 8.90 (1H, d, J = 1.26Hz) 8.39 (1H, s) 7.97 (1H, d, J = 1.52 Hz) 7.18 (2H, s) 6.57 (2H, s)5.95-6.11 (1H, m) 2.55 (3H, s) 2.25 (2H, dd, J = 11.12, 7.58 Hz)1.95-2.11 (2H, m) 1.71-1.83 (2H, m) 1.59 (2H, dd, J = 9.98, 5.18 Hz) 231A

2-Amino-6-(6-chloro- pyridin-2-yl)-8- cyclopentyl-4-methyl-8H-pyrido[2,3- d]pyrimidin-7-one 356 (400 MHz, CHLOROFORM- d) δ ppm 8.56(1H, s) 8.29 (1H, d, J = 7.83 Hz) 7.61 (1H, t, J = 7.83 Hz) 7.16 (1H, s)5.80- 6.02 (1H, m) 5.09-5.25 (2H, m) 2.61 (3H, s) 2.25 (2H, dd, J =11.62, 7.58 Hz) 2.02 (2 H, dd, J = 7.71, 4.93 Hz) 1.71- 1.86 (2H, m)1.55-1.66 (2H, m). 232 A

8-(2-Cyclopropyl- ethyl)-6-(6-methoxy- pyridin-3-yl)-4-methyl-2-methylamino-8H- pyrido[2,3-d]pyrimidin- 7-one 366 (400 MHz,CHLOROFORM- d) δ ppm 10.27 (1H, s) 8.35 (1H, d, J = 2.27 Hz) 7.92 (1H,dd, J = 8.59, 2.53 Hz) 7.65 (1H, s) 6.83 (1H, d, J = 8.84 Hz) 4.42-4.61(2H, m) 3.99 (3H, s) 3.13 (3H, d, J = 4.29 Hz) 2.77 (3H, s) 1.65 (2H, q,J = 7.16 Hz) 0.68-0.89 (1H, m) 0.38-0.55 (2H, m) 0.08 (2H, q, J = 4.88Hz) 233 A

2-Amino-8-(2- cyclopropyl-ethyl)-6- (6-methoxy-pyridin-3-yl)-4-methyl-8H- pyrido[2,3-d]pyrimidin- 7-one 352 (400 MHz, DMSO-d6) δppm 8.40 (1H, d, J = 2.02 Hz) 7.91- 8.05 (2H, m) 7.09 (2H, s) 6.79 (1H,d, J = 8.59 Hz) 4.24- 4.40 (2H, m) 3.82 (3H, s) 2.50 (3H, s) 1.46 (2H,q, J = 7.07 Hz) 0.59-0.77 (1H, m) 0.27-0.39 (2H, m) -0.01 (2H, d, J =4.55 Hz) 234 A

8-Cyclopentyl-4- methyl-2- methylamino-6-(1- methyl-1H-pyrazol-4-yl)-8H-pyrido[2,3- d]pyrimidin-7-one 339 (400 MHz, CHLOROFORM- d) δ ppm8.28 (1H, s) 7.87 (2H, s) 5.99-6.26 (1H, m) 5.24 (1H, d, J = 3.03 Hz)3.95 (3H, s) 3.08 (3H, d, J = 5.05 Hz) 2.62 (3H, s) 2.44 (2H, s)2.02-2.21 (2H, m) 1.78- 1.95 (2H, m) 1.65-1.77 (2H, m) 235 A

2-Amino-8- cyclopentyl-4-methyl- 6-(1-methyl-1H- pyrazol-4-yl)-8H-pyrido[2,3-d]pyrimidin- 7-one 325 (400 MHz, CHLOROFORM- d) δ ppm 8.28(1H, s) 7.87 (2H, s) 6.04 (1H, d, J = 8.59 Hz) 5.11 (2H, s) 3.95 (3H, s)2.64 (3H, s) 2.34 (2H, dd, J = 11.49, 7.20 Hz) 2.03-2.17 (2H, m)1.80-1.96 (2H, m) 1.65-1.77 (2H, m) 236 A

8-Cyclopentyl-6-[1- (2,2-difluoro-ethyl)-1H- pyrazol-4-yl]-4-methyl-2-methylamino-8H- pyrido[2,3 d]pyrimidin- 7-one 389 (400 MHz,CHLOROFORM- d) δ ppm 8.30 (1H, s) 7.88 (1H, s) 7.80 (1H, s) 5.84-6.30(2H, m) 5.19 (1H, s) 4.29- 4.55 (2H, m) 3.00 (3H, d, J = 5.05 Hz) 2.54(3H, s) 2.37 (2H, s) 1.94-2.09 (2H, m) 1.74-1.89 (2H, m) 1.58- 1.69 (2H,m) 237 A

2-Amino-8- cyclopentyl-6-[1-(2,2- difluoro-ethyl)-1H-pyrazol-4-yl]-4-methyl- 8H-pyrido[2,3- d]pyrimidin-7-one 375 (400 MHz,CHLOROFORM- d) δ ppm 8.38 (1H, s) 7.97 (1H, s) 7.89 (1H, s) 5.89-6.34(2H, m) 5.13 (2H, s) 4.35- 4.60 (2H, m) 2.64 (3H, s) 2.24-2.45 (2H, m)2.04- 2.21 (2H, m) 1.80-1.96 (2H, m) 1.66-1.79 (2H, m) 238 E

2-Amino-8-(2-amino- ethyl)-6-(6-methoxy- pyridin-3-yl)-4-methyl-8H-pyrido[2,3- d]pyrimidin-7-one 327 (400 MHz, DMSO-d6) δ ppm 8.48 (1H,d, J = 2.27 Hz) 7.92- 8.08 (2H, m) 7.17 (2H, s) 6.86 (1H, d, J = 8.59Hz) 4.33 (2H, t, J = 6.82 Hz) 3.88 (3H, s) 2.84 (2H, t, J = 6.82 Hz)2.57 (2H, s) 1.88 (3H, s) 239 E

8-(2-Amino-ethyl)-6- (6-methoxy-pyridin-3- yl)-4-methyl-2-methylamino-8H- pyrido[2,3-d]pyrimidin- 7-one 341 (400 MHz, DMSO-d6) δppm 8.48 (1H, s) 7.94-8.10 (2H, m) 7.70 (1H, s) 6.85 (1H, d, J = 8.59Hz) 4.25-4.49 (2H, m) 3.88 (3H, s) 2.89 (5H, d, J = 4.80 Hz) 2.54-2.66(3H, m) 240 Similar to Exam- ple 31

2-Amino-8- cyclopentyl-6-[1-(2- hydroxy-2-methyl- propyl)-1H-pyrazol-4-yl]-4-methyl-8H- pyrido[2,3-d]pyrimidin- 7-one 383 (400 MHz, DMSO-d6) δppm 8.37 (1H, s) 8.12 (1H, s) 8.09 (1H, s) 7.05 (2H, s) 5.96-6.11 (1H,m) 4.72 (1H, s) 4.03 (2H, s) 2.58 (3H, s) 2.15-2.31 (2H, m) 1.96- 2.09(2H, m) 1.68-1.82 (2H, m) 1.54-1.65 (2H, m) 1.07 (6H, s) 241 E

2-Amino-8-isobutyl-6- (6-methoxy-pyridin-3- yl)-4-methyl-8H-pyrido[2,3-d]pyrimidin- 7-one 340 (400 MHz, DMSO-d6) δ ppm 8.47 (1H, d,J = 2.53 Hz) 7.98- 8.07 (2H, m) 7.15 (2H, br. s.) 6.86 (1H, d, J = 8.59Hz) 4.17 (2H, d, J = 7.33 Hz) 3.88 (3H, s) 2.57 (3H, s) 2.16- 2.30 (1H,m) 0.87 (6H, d, J = 6.82 Hz) 242 E

2-Amino-6-(6- methoxy-pyridin-3-yl)- 4-methyl-8- (tetrahydro-pyran-4-ylmethyl)-8H- pyrido[2,3-d]pyrimidin- 7-one 382 (400 MHz, DMSO-d6) δ ppm8.47 (1H, d, J = 2.53 Hz) 7.99- 8.09 (2H, m) 7.18 (2H, s) 6.86 (1H, d, J= 8.59 Hz) 4.24 (2H, d, J = 7.07 Hz) 3.88 (3H, s) 3.77-3.86 (2H, m) 3.20(2H, td, J = 11.43, 2.15 Hz) 2.56 (3H, s) 2.05-2.17 (1H, m) 1.30-1.51(4H, m) 243 E

2-Amino-8-(4-fluoro- tetrahydro-pyran-4- ylmethyl)-6-(6-methoxy-pyridin-3-yl)- 4-methyl-8H- pyrido[2,3-d]pyrimidin- 7-one 400(400 MHz, DMSO-d6) δ ppm 8.47 (1H, d, J = 2.53 Hz) 8.06 (1H, s) 8.03(1H, dd, J = 8.59, 2.53 Hz) 7.22 (2H, br. s.) 6.87 (1H, d, J = 8.59 Hz)4.66 (2H, d, J = 18.19 Hz) 3.89 (3H, s) 3.69-3.76 (2H, m) 3.45-3.54 (2H,m, J = 11.37, 11.37, 1.52 Hz) 2.57 (3H, s) 1.74-1.94 (2H, m) 1.59-1.73(2H, m) 244 E

2-Amino-8-(2-fluoro-2- methyl-propyl)-6-(6- methoxy-pyridin-3-yl)-4-methyl-8H- pyrido[2,3-d]pyrimidin- 7-one 358 (400 MHz, DMSO-d6) δ ppm8.47 (1H, d, J = 2.02 Hz) 8.06 (1H, s) 8.02 (1H, dd, J = 8.72, 2.40 Hz)7.19 (2H, s) 6.86 (1H, d, J = 8.84 Hz) 4.64 (2H, d, J = 17.94 Hz) 3.88(3H, s) 2.57 (3H, s) 1.37 (3H, s) 1.31 (3H, s) 245 C

8-Cyclopentyl-4- methyl-2- methylamino-6-(2- methyl-1H-imidazol-4-yl)-8H-pyrido[2,3- d]pyrimidin-7-one 339 (400 MHz, ETHANOL-d6) δ ppm8.41 (1H, s) 7.74 (1H, s) 6.09-6.22 (1H, m) 5.50 (1H, s) 3.01 (3H, s)2.65 (3H, s) 2.47 (5H, s) 2.12 (2H, dd, J = 7.96, 5.43 Hz) 1.82- 1.94(2H, m) 1.67-1.79 (2H, m) 246 F

3-[2-Amino-6-(6- methoxy-pyridin-3-yl)- 4-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidin- 8-yl]-pyrrolidine-1- carboxylic acid tert- butylester (400 MHz, DMSO-d6) δ ppm 8.43 (1H, d, J = 2.53 Hz) 7.94- 8.07 (2H,m) 7.21 (2H, br. s.) 6.85 (1H, d, J = 8.59 Hz) 6.16-6.31 (1H, m) 3.88(3H, s) 3.76 (1H, t, J = 9.09 Hz) 3.59-3.71 (1H, m) 3.51 (1H, t, J =9.60 Hz) 2.63-2.76 (1H, m) 2.56 (3H, s) 2.06 (1H, d, J = 14.15 Hz) 1.40(9H, d, J = 12.13 Hz) (one proton is under water peak) 253 G

2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-6-(6-pyrrolidin-1-ylpyridin-3- yl)pyrido[23- d]pyrimidin-7(8H)-one 421 (500 MHz,DMSO-d6) δ ppm 1.24-1.35 (m, 2H) 1.48 (d, J = 11.81 Hz, 2H) 1.88-1.98(m, 6H) 3.33-3.43 (m, 4H) 4.80-4.88 (m, 1H) 6.46 (d, J = 8.52 Hz, 1H)6.92 (br. s., 2H) 7.78 (dd, J = 8.93, 2.33 Hz, 1H) 7.80 (s, 1H) 8.30 (d,J = 1.65 Hz, 1H). Three aliphatic and one methyl residue not visible dueto overlap with solvent and water resonances. 254 G

2-amino-8- cyclopentyl-6-(5- fluoro-6- methoxypyridin-3-yl)-4-methylpyrido[23- d]pyrimidin-7(8H)-one 370 (500 MHz, DMSO-d6) δ ppm1.51-1.62 (m, 2H) 1.69- 1.82 (m, 2H) 1.92-2.06 (m, 2H) 2.14-2.25 (m, 2H)3.96 (s, 3H) 5.96 (d, J = 8.79 Hz, 1H) 7.04 (br. s., 2H) 7.96 (d, J =11.81 Hz, 1H)8.02 (s, 1H) 8.26 (d, J = 1.65 Hz, 1H). One methyl residuenot visible due to overlap with solvent resonance 255 G

2-amino-8- cyclopentyl-6-(2- methoxypyrimidin-5- yl)-4-methylpyrido[23-d]pyrimidin-7(8H)-one 353 (500 MHz, DMSO-d6) δ ppm 1.51-1.63 (m, 2H)1.69- 1.81 (m, 2H) 1.93-2.06 (m, 2H) 2.12-2.26 (m, 2H) 3.94 (s, 3H)5.91-5.99 (m, 1H) 7.05 (br. s., 2H) 8.08 (s, 1H) 8.84 (s, 2H). Onemethyl residue not visible due to overlap with solvent resonance. 256 G

2-amino-8- cyclopentyl-6-[3- (hydroxymethyl)phenyl]- 4-methylpyrido[23-d]pyrimidin-7(8H)-one 351 (500 MHz, DMSO-d6) δ ppm 1.58 (br. s., 2H)1.75 (d, J = 9.61 Hz, 2H) 1.99 (br. s., 2H) 2.14-2.26 (m, 2H) 4.53 (d, J= 5.49 Hz, 2H) 5.31- 5.38 (m, 1H) 5.90-6.03 (m, 1H) 6.98 (br. s., 2H)7.27 (d, J = 7.69 Hz, 1H) 7.35 (t, J = 7.69 Hz, 1H) 7.48 (d, J = 7.42Hz, 1H) 7.55 (s, 1H) 7.87 (s, 1H). One methyl residue not visible due tooverlap with solvent resonance. 257 G

2-amino-8- cyclopentyl-6-[6- (dimethylamino)-5- methylpyridin-3-yl]-4-methylpyrido[23- d]pyrimidin-7(8H)-one 379 (500 MHz, DMSO-d6) δ ppm1.52-1.63 (m, 2H) 1.69- 1.80 (m, 2H) 1.93-2.04 (m, 2H) 2.14-2.24 (m, 2H)2.27 (s, 3H) 2.80 (s, 6H) 5.95 (quin, 1H) 6.96 (d, J = 1.37 Hz, 2H) 7.72(d, J = 1.92 Hz, 1H) 7.89 (s, 1H) 8.27 (d, J = 2.20 Hz, 1H). One methylresidue not visible due to overlap with solvent resonance. 258 G

2-amino-8- cyclopentyl-4-methyl- 6-(6-pyrrolidin-1- ylpyridin-3-yl)pyrido[23- d]pyrimidin-7(8H)-one 391 (500 MHz, DMSO-d6) δ ppm1.52-1.63 (m, 2H) 1.69- 1.80 (m, 2H) 1.88-1.98 (m, 4H) 1.96-2.05 (m, 2H)2.16- 2.25 (m, 2H) 3.37 (br. s., 2H) 5.95 (m, 1H) 6.47 (d, J = 9.06 Hz,1H) 6.89 (br. s., 2H) 7.80 (d, J = 9.06 Hz, 1H) 8.23 (s, 1H) 8.30 (s,1H). Two aliphatic protons and one methyl residue not visible due tooverlap with solvent and water resonances. 259 G

2-amino-6-(2- methoxypyrimidin-5- yl)-4-methyl-8- (tetrahydro-2H-pyran-4-yl)pyrido[23- d]pyrimidin-7(8H)-one 369 (500 MHz, DMSO-d6) δ ppm 1.49(d, J = 13.46 Hz, 2H) 2.99 (m, 2H) 3.96 (s, 3H) 3.97-4.02 (m, 2H) 5.60-5.78 (m, 1H) 7.19 (s, 2H) 8.13 (s, 1H) 8.88 (s, 2H). One methyl residueand two aliphatic protons not visible due to overlap with solventresonace. 260 G

2-amino-6-[3- (hydroxymethyl)phenyl]- 4-methyl-8- (tetrahydro-2H-pyran-4-yl)pyrido[23- d]pyrimidin-7(8H)-one 367 (500 MHz, DMSO-d6) δ ppm 1.48(d, J = 11.26 Hz, 2H) 2.87-3.07 (m, 2H) 4.00 (dd, J = 11.54, 4.12 Hz,2H) 4.54 (d, J = 5.22 Hz, 2H) 5.12- 5.30 (m, 1H) 5.66-5.73 (m, 1H) 7.10(s, 2H) 7.29 (d, J = 7.69 Hz, 1H) 7.35 (t, J = 7.55 Hz, 1H) 7.50 (d, J =7.69 Hz, 1H) 7.58 (s, 1H) 7.89 (s, 1H). One methyl residue and twoaliphatic protons not visible due to overlap with solvent resonance. 261G

2-amino-6-(2,3- dihydro-1,4- benzodioxin-6-yl)-8- (trans-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 409 (500MHz, DMSO-d6) δ ppm 1.29 (q, J = 13.00 Hz, 2H) 1.48 (d, J = 10.16 Hz,2H) 1.92 (d, J = 12.36 Hz, 2H) 4.24 (s, 4H) 4.84 (br. s., 1H) 5.37 (br.s., 1H) 6.85 (d, J = 8.52 Hz, 1H) 6.96 (br. s., 2H) 7.09 (dd, J = 8.52,1.92 Hz, 1H) 7.16 (d, J = 1.92 Hz, 1H) 7.79 (s, 1H). One methyl residueand three aliphatic protons not visible due to overlap with solventresonance. 262 G

2-amino-8- cyclopentyl-6-(3- fluoro-4- methoxyphenyl)-4-methylpyrido[23- d]pyrimidin-7(8H)-one 369 (500 MHz, DMSO-d6) δ ppm1.48-1.65 (m, 2H) 1.68- 1.82 (m, 2H) 1.91-2.09 (m, 2H) 2.12-2.28 (m, 2H)3.85 (s, 3H) 5.92-5.98 (m, 1H) 6.98 (br. s., 2H) 7.16 (t, J = 8.93 Hz,1H) 7.45 (d, J = 7.97 Hz, 1H) 7.54 (dd, J = 13.19, 1.92 Hz, 1H) 7.90 (s,1H). One methyl residue not visible due to overlap with solvent andwater resonances. 265 F

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)- 4-methyl-8-(tetrahydro-2H-pyran- 4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 386 (400MHz, DMSO-d6) δ ppm 8.28-8.36 (1H, m) 8.08 (1H, s) 8.01 (1H, dd, J =12.13, 2.02 Hz) 7.25 (2H, s) 5.57- 5.82 (1H, m) 4.00-4.05 (2H, m) 3.98(3H, s) 3.40 (2H, t, J = 11.37 Hz) 2.87-3.07 (2H, m) 2.57 (3H, s) 1.48(2H, d, J = 9.60 Hz 266 E

2-amino-8-isopropyl-6- (2-methoxypyrimidin- 5-yl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 327 (400 MHz, CHLOROFORM- d) δ ppm 8.80 (2H, s)7.75 (1H, s) 5.75-6.00 (1H, m) 5.58 (2H, br. s.) 4.06 (3H, s) 2.66 (3H,s) 1.61 (6H, d, J = 6.82 Hz) 268 Similar to Exam- ple 60

2-amino-6-(2- hydroxypyrimidin-5- yl)-8-isopropyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one 313 (400 MHz, DMSO-d₆) δ ppm 12.12 (1H, br. s.)8.63 (2H, br. s.) 8.09 (1H, s) 7.19 (2H, br. s.) 5.48-6.13 (1H, m) 2.55(3H, s) 1.51 (6H, d, J = 6.82 Hz) 271 F

2-amino-8-(trans-4- hydroxycyclohexyl)-4- methyl-6-(quinolin-3-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 402 (400 MHz, DMSO-d6) d ppm1.24-1.38 (m, 2H) 1.51- 1.60 (m, 2H) 1.92-1.99 (m, 2H) 2.59 (s, 3H)2.68-2.92 (m, 2H) 3.49-3.66 (m, 1H) 4.47-4.85 (m, 1H) 5.24- 5.68 (m, 1H)7.25 (br. s., 2H) 7.60-7.67 (m, 1H) 7.73- 7.79 (m, 1H) 8.00-8.06 (m, 2H)8.23 (s, 1H) 8.64 (d, J = 1.77 Hz, 1H) 9.16 (d, J = 2.27 Hz, 1H) 272 F

2-amino-8-(cis-4- hydroxycyclohexyl)-6- (2-methoxypyrimidin- 5-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 383 (400 MHz, DMSO-d6) δ ppm1.21-1.31 (m, 2H) 1.45- 1.56 (m, 2H) 1.75-1.84 (m, 2H) 2.56 (s, 3H)2.96-3.08 (m, 2H) 3.85-3.91 (m, 1H) 3.95 (s, 3H) 4.32 (d, J = 2.27 Hz,1H) 5.41-5.52 (m, 1H) 7.19 (s, 2H) 8.12 (s, 1H) 8.89 (s, 2H) 273 F

2-amino-8-(trans-4- hydroxycyclohexyl)-6- (2-methoxypyrimidin- 5-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 383 (400 MHz, DMSO-d6) δ ppm1.23-1.34 (m, 2H) 1.47- 1.57 (m, 2H) 1.88-1.98 (m, 2H) 2.55 (s, 3H)2.71-2.82 (m, 2H) 3.47-3.59 (m, 1H) 3.95 (s, 3H) 4.60 (d, J = 4.04 Hz,1H) 5.17-5.73 (m, 1H) 7.22 (s, 2H) 8.12 (s, 1H) 8.87 (s, 2H) 274 A

8-(trans-4- hydroxycyclohexyl)-6- (6-methoxypyridin-3- yl)-4-methyl-2-(methylamino)pyrido [2,3-d]pyrimidin- 7(8H)-one 396 (400 MHz, DMSO-d6) δppm 1.25-1.35 (m, 2H) 1.47- 1.59 (m, 2H) 1.89-2.00 (m, 2 H) 2.54 (s, 3H)2.69-2.79 (m, 2H) 2.85-2.95 (m, 3H) 3.43-3.52 (m, 1H) 3.88 (s, 3H) 4.63(d, J = 4.29 Hz, 1H) 5.04-5.91 (m, 1H) 6.84 (d, J = 8.59 Hz, 1H) 7.70(d, J = 4.55 Hz, 1H) 7.97 (s, 1H) 7.98-8.03 (m, 1H) 8.43 (s, 1H) 276 A

2-(ethylamino)-6-(5- fluoro-6- methoxypyridin-3-yl)- 8-(trans-4-hydroxycyclohexyl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 428 (400MHz, DMSO-d6) δ ppm 1.15-1.21 (m, 3H) 1.23- 1.35 (m, 2H) 1.49-1.60 (m,2H) 1.90-1.99 (m, 2H) 2.55 (s, 3H) 2.69-3.03 (m, 2H) 3.34-3.42 (m, 2H)3.43- 3.54 (m, 1H) 3.98 (s, 3H) 4.64 (d, J = 4.04 Hz, 1H) 5.11- 5.66 (m,1H) 7.85 (t, J = 5.68 Hz, 1H) 8.02 (d, J = 12.13 Hz, 1H) 8.06 (s, 1H)8.31 (s, 1H) 277 A

2-(ethylamino)-8- (trans-4- hydroxycyclohexyl)-6- (2-methoxypyrimidin-5-yl)-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 411 (300 MHz, DMSO-d6)δ ppm 1.18 (t, J = 6.97 Hz, 3H) 1.23- 1.38 (m, 2H) 1.45-1.61 (m, 2H)1.88-2.03 (m, 2H) 2.55 (s, 3H) 2.67-3.06 (m, 2H) 3.35-3.44 (m, 2H) 3.44-3.58 (m, 1H) 3.95 (s, 3H) 4.64 (d, J = 4.14 Hz, 1H) 5.15- 5.56 (m, 1H)7.84-7.92 (m, 1H) 8.13 (s, 1H) 8.89 (s, 2H) 278 Similar to Exam- ple 85

2-amino-N-(1-ethyl- 1H-pyrazol-5-yl)-8- (trans-4- hydroxycyclohexyl)-4-methyl-7-oxo-78- dihydropyrido[23- d]pyrimidine-6- carboxamide 412 (400MHz, DMSO-d 6) ppm 1.31 (d, J = 14.65 Hz, 4H), 1.38 (t, J = 7.20 Hz,3H), 1.57 (d, J = 11.87 Hz, 2H), 1.96 (d, J = 12.13 Hz, 2H), 2.62 (s,3H), 3.13-3.23 (m, 1H), 4.05-4.16 (m, 2H), 4.64 (s, 1H), 6.43 (d, J =1.26 Hz, 1H), 7.39 (d, J = 1.77 Hz, 1H), 7.75 (d, J = 14.65 Hz, 2H),8.79 (s, 1H), 12.01 (s, 1H) 279 Similar to Exam- ple 85

2-amino-8-isopropyl-4- methyl-7-oxo-N-1H- pyrazol-5-yl-7,8-dihydropyrido[2,3- d]pyrimidine-6- carboxamide 328 (400 MHz, DMSO-d 6 )δ ppm 1.57 (d, J = 6.82 Hz, 6H) 2.62 (s, 3H) 5.90 (br. s., 1H) 6.66 (t,J = 2.02 Hz, 1H) 7.67 (s, 1H) 7.71 (br. s., 2H) 8.80 (s, 1H) 11.92 (s,1H) 12.48 (br. s., 1H) 280 Similar to Exam- ple 85

2-amino-N-(1-ethyl- 1H-pyrazol-5-yl)-8- isopropyl-4-methyl-7- oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6- carboxamide 356 (400 MHz, DMSO-d 6) δppm 1.38 (t, J = 7.20 Hz, 3H) 1.58 (d, J = 6.82 Hz, 6H) 2.63 (s, 3H)4.10 (q, J = 7.33 Hz, 2H) 5.89 (br. s., 1H) 6.45 (d, J = 1.77 Hz, 1H)7.38 (d, J = 1.77 Hz, 1H) 7.77 (d, J = 15.41 Hz, 2H) 8.80 (s, 1H) 12.14(s, 1H) 281 Similar to Exam- ple 85

8-cyclopentyl-N-[(1- ethyl-1H-pyrazol-4- yl)methyl]-4-methyl-2-(methylamino)-7-oxo- 7,8-dihydropyrido[2,3- d]pyrimidine-6- carboxamide410 (400 MHz, DMSO-d 6 ) δ ppm 1.35 (t, J = 7.20 Hz, 3H) 1.48-1.69 (m,2H) 1.71- 1.86 (m, 2H) 1.89-2.09 (m, 2H) 2.12-2.39 (m, 2H) 2.59 (s, 2H)2.64 (s, 1H) 2.91 (s, 3H) 4.09 (q, J = 7.33 Hz, 2H) 4.35 (d, J = 5.56Hz, 2H) 5.88- 6.06 (m, 1H) 7.40 (s, 1H) 7.69 (s, 1H) 7.84-7.97 (m, 0.3H)8.14 (q, J = 4.38 Hz, 0.7H) 8.71 (s, 1H) 9.48-9.73 (m, 1H) 282 Similarto Exam- ple 85

8-cyclopentyl-4- methyl-2- (methylamino)-7-oxo- N-pyridin-2-yl-7,8-dihydropyrido[2,3- d]pyrimidine-6- carboxamide 379 (400 MHz, DMSO-d 6 )d ppm 1.62-1.79 (m, 2H) 1.82- 1.95 (m, 2H) 1.99-2.18 (m, 2H) 2.23-2.47(m, 2H) 2.68 (s, 2H) 2.74 (s, 1H) 2.96-3.03 (m, 3H) 5.99- 6.26 (m, 1H)7.12-7.28 (m, 1H) 7.90 (s, 1H) 8.08-8.17 (m, 0.3H) 8.22-8.37 (m, 1.7H)8.41 (d, J = 4.04 Hz, 1H) 8.88 (s, 1H) 12.23 (s, 1H) 283 Similar toExam- ple 85

8-cyclopentyl-N- isoxazol-3-yl-4-methyl- 2-(methylamino)-7- oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6- carboxamide 369 (400 MHz, DMSO-d 6 )d ppm 1.49-1.73 (m, 2H) 1.76- 1.90 (m, 2H) 1.95-2.12 (m, 2H) 2.18-2.39(m, 2H) 2.63 (s, 2H) 2.68 (s, 1H) 2.91-2.98 (m, 3H) 5.94- 6.12 (m, 1H)7.08 (d, J = 1.77 Hz, 1H) 8.13 (m, 0.3H) 8.35 (q, J = 4.38 Hz, 0.7H)8.81 (s, 1H) 8.88 (d, J = 1.77 Hz, 1H) 12.31 (s, 1H) 286 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]-6-(6-methoxypyridin-3-yl)- 4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 426 (400MHz, DMSO-d₆) δ ppm 1.21-1.31 (m, 2H) 1.53- 1.60 (m, 2H) 2.07-2.14 (m,2H) 2.55 (s, 3H) 2.69-2.90 (m, 2H) 3.45-3.50 (m, 5H) 3.88 (s, 3H) 4.56(t, J = 5.43 Hz, 1H) 5.32-5.53 (m, 1H) 6.84 (d, J = 9.09 Hz, 1H) 7.15(br. s., 2H) 7.97 (s, 1H) 8.00 (dd, J = 8.59, 2.53 Hz, 1H) 8.42 (d, J =2.27 Hz, 1H) 287 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]-6-(2-methoxypyrimidin-5- yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 427(400 MHz, DMSO-d₆) δ ppm 1.20-1.31 (m, 2H) 1.53- 1.60 (m, 2H) 2.06-2.14(m, 2H) 2.56 (s, 3H) 2.66-2.86 (m, 2H) 3.45-3.56 (m, 5H) 3.95 (s, 3H)4.54 (t, 1H) 5.31-5.53 (m, 1H) 7.22 (br. s., 2H) 8.13 (s, 1H) 8.88 (s,2H) 288 I

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)- 8-[trans-4-(2-hydroxyethoxy) cyclohexyl]-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one444 (300 MHz, DMSO-d₆) δ ppm 1.15-1.35 (m, 2H) 1.49- 1.63 (m, 2H)2.06-2.16 (m, 2H) 2.56 (s, 3H) 2.70-2.92 (m, 2H) 3.34-3.43 (m, 1H)3.43-3.53 (m, 4H) 3.98 (s, 3H) 4.56 (t, 1H) 5.30-5.58 (m, 1H) 7.21 (br.s., 2H) 8.00 (dd, J = 12.34, 1. Hz, 1H) 8.06 (s, 1H) 8.31 (d, J = 1.88Hz, 1H) 289 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]-4-methyl-6-quinolin-3- ylpyrido[2,3- d]pyrimidin-7(8H)-one 446 (400 MHz, DMSO-d₆) δppm 1.21-1.35 (m, 2H) 1.57- 1.66 (m, 2H) 2.07-2.18 (m, 2H) 2.60 (s, 3H)2.73-2.95 (m, 2H) 3.40-3.53 (m, 5H) 4.57 (t, J = 5.18 Hz, 1H) 5.37- 5.60(m, 1H) 7.25 (br. s., 2H) 7.63 (t, J = 6.95 Hz, 1H) 7.76 (t, J = 7.71Hz, 1H) 8.03 (t, J = 7.07 Hz, 2H) 8.24 (s, 1H) 8.65 (d, J = 2.02 Hz, 1H)9.17 (d, J = 2.27 Hz, 1H) 290 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]- 4-methyl-6-(1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 385 (400 MHz, DMSO-d6) δppm 1.20-1.37 (m, 2H) 1.50-1.61 (m, 2H) 2.07-2.18 (m, 2H) 2.57 (s, 3H)2.69-2.93 (m, 2H) 3.36-3.45 (m, 1H) 3.45-3.54 (m, 4H) 4.56 (t, J = 5.31Hz, 1H) 5.35- 5.58 (m, 1H) 7.03 (br. s., 2H) 8.11 (s, 1H) 8.13 (br. s.,1H) 8.34 (br. s., 1H) 12.85 (br. s., 1H) 291 I

2-amino-6-bromo-8- [trans-4-(2- hydroxyethoxy) cyclohexyl]-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 397, 399 (400 MHz, DMSO-d₆) δppm 1.17-1.30 (m, 2H) 1.51- 1.59 (m, 2H) 2.07-2.14 (m, 2H) 2.49 (br. s.,3H) 2.63- 2.76 (m, 2H) 3.35-3.41 (m, 1H) 3.45-3.52 (m, 4H) 4.56 (t, 1H)5.33-5.55 (m, 1H) 7.26 (br. s., 2H) 8.35 (s, 1H) 292 I

2-amino-6-[6- (dimethylamino)pyridin- 3-yl]-8-[trans-4-(2-hydroxyethoxy) cyclohexyl]-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one439 (400 MHz, DMSO-d₆) δ ppm 1.19-1.32 (m, 2H) 1.51- 1.60 (m, 2H)2.06-2.15 (m, 2H) 2.54 (s, 3H) 2.67-2.88 (m, 2H) 3.05 (s, 6H) 3.40- 3.52(m, 5H) 4.56 (t, J = 5.43 Hz, 1H) 5.31-5.54 (m, 1H) 6.65 (d, J = 8.84Hz, 1H) 7.07 (br. s., 2H) 7.84 (dd, J = 8.84, 2.53 Hz, 1H) 7.86 (s, 1H)8.37 (d, J = 2.53 Hz, 1H) 293 I

2-amino-8-[cis-4-(2- hydroxyethoxy) cyclohexyl]-6-(2-methoxypyrimidin-5- yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 427(400 MHz, DMSO-d6) δ ppm 1.21-1.34 (m, 2H) 1.38- 1.50 (m, 2H) 1.90-2.05(m, 2H) 2.56 (s, 3H) 2.88-3.12 (m, 2H) 3.42 (t, J = 5.18 Hz, 2H) 3.58(d, J = 5.81 Hz, 3H) 3.95 (s, 3H) 4.54-4.76 (m, 1H) 5.36-5.59 (m, 1H)7.04- 7.38 (m, 2H) 8.12 (s, 1H) 8.88 (s, 2H) 294 I

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)- 8-[cis-4-(2- hydroxyethoxy)cyclohexyl]-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one 444 (400 MHz,DMSO-d6) δ ppm 1.22-1.35 (m, 2H) 1.37- 1.51 (m, 2H) 1.96-2.05 (m, 2H)2.56 (s, 3H) 2.88-3.12 (m, 2H) 3.43 (t, J = 5.18 Hz, 2H) 3.51-3.63 (m,3H) 3.98 (s, 3H) 4.54-4.78 (m, 1H) 5.35-5.57 (m, 1H) 7.04- 7.27 (m, 2H)8.01 (dd, J = 12.25, 1.89 Hz, 1H) 8.06 (s, 1H) 8.31 (d, J = 1.77 Hz, 1H)295 I

2-amino-8-[cis-4-(2- hydroxyethoxy) cyclohexyl]-4-methyl-6- quinolin-3-ylpyrido[2,3- d]pyrimidin-7(8H)-one 446 (400 MHz, DMSO-d6) δ ppm1.22-1.38 (m, 2H) 1.39- 1.52 (m, 2H) 1.96-2.08 (m, 2H) 2.59 (s, 3H)2.91-3.14 (m, 2H) 3.43 (t, J = 5.05 Hz, 2H) 3.52-3.65 (m, 3H) 4.51- 4.75(m, 1H) 5.41-5.61 (m, 1H) 7.07-7.31 (m, 2H) 7.62 (t, J = 7.96 Hz, 1H)7.76 (td, J = 7.64, 1.39 Hz, 1H) 8.03 (d, J = 8.34 Hz, 2H) 8.22 (s, 1H)8.63 (d, J = 2.02 Hz, 1H) 9.16 (d, J = 2.02 Hz, 1H) 296 I

2-amino-8-[cis-4-(2- hydroxyethoxy) cyclohexyl]-4- methyl-6-(1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 385 (400 MHz, DMSO-d6) δppm 1.22-1.31 (m, 2H) 1.41- 1.51 (m, 2H) 1.96-2.05 (m, 2H) 2.57 (s, 3H)2.91-3.13 (m, 2H) 3.44 (t, J = 5.18 Hz, 2H) 3.57-3.62 (m, 3H) 4.57- 4.79(m, 1H) 5.37-5.56 (m, 1H) 6.83-7.06 (m, 2H) 8.10 (s, 1H) 8.13 (s, 1H)8.34 (s, 1H) 12.85 (br. s., 1H) 297 I

methyl 2-(trans-amino- 6-bromo-4-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)- yl)cyclohexyloxy) acetate 425 (400 MHz, DMSO-d 6) ppm1.18-1.35 (m, 2H) 1.55 (d, J = 11.37 Hz, 2H) 2.13 (d, J = 10.36 Hz, 2H)3.67 (s, 3H) 4.18 (s, 2H) 5.47 (br. s., 1H) 7.27 (br. s., 2H) 8.35 (s,1H) 298 I

methyl ({trans-4-[2- amino-6-(5-fluoro-6- methoxypyridin-3-yl)-4-methyl-7- oxopyrido[2,3- d]pyrimidin-8(7H)- yl[cyclohexyl}oxy) acetate472.2 (400 MHz, DMSO-d 6) ppm 1.21-1.40 (m, 2H) 1.58 (d, J = 10.36 Hz,2H) 2.14 (d, J = 9.85 Hz, 2H) 2.57 (s, 3H) 2.69-2.87 (m, 2H) 3.46 (dd, J= 13.26, 8.97 Hz, 1H) 3.67 (s, 3H) 3.99 (s, 3H) 4.18 (s, 2H) 5.47 (br.s., 1H) 7.22 (br. s., 2H) 8.01 (dd, J = 12.25, 1.89 Hz, 1H) 8.07 (s, 1H)8.32 (d, J = 2.02 Hz, 1H) 299 I

2-({trans-4-[2-amino- 6-(5-fluoro-6- methoxypyridin-3-yl)- 4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 457.2(400 MHz, DMSO-d 6) ppm 1.27-1.46 (m, 2H) 1.64 (d, J = 10.61 Hz, 2H)2.22 (d, J = 10.61 Hz, 2H) 2.63 (s, 3H) 2.85 (br. s., 2H) 3.44-3.64 (m,1H) 3.91 (s, 2H) 4.05 (s, 3H) 5.52 (br. s., 1H) 7.15 (br. s., 1H) 7.28(br. s., 2H) 7.38 (br. s., 1H) 8.07 (dd, J = 12.25, 1.89 Hz, 1H) 8.13(s, 1H) 8.38 (d, J = 2.02 Hz, 1H) 300 I

2-amino-8-(trans-4- {[(2S)-2,3- dihydroxypropyl]oxy} cyclohexyl)-6-(6-methoxypyridin-3-yl)- 4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 456 (400MHz, CHLOROFORM- d) δ ppm 1.45 (m, 2H) 1.71 (m, 2H) 2.15-2.26 (m, 3H)2.60 (s, 3H) 2.68 (d, J = 5.05 Hz, 1H) 2.82 (bs, 2H) 3.44 (m, 1H)3.57-3.75 (m, 4H) 3.87 (m, 1H) 3.98 (s, 3H) 5.22 (s, 2H) 5.51 (bs, 1H)6.80 (d, J = 8.84 Hz, 1H) 7.71- 7.78 (m, 1H) 7.96 (dd, J = 8.72, 2.40Hz, 1H) 8.30 (d, J = 2.02 Hz, 1H) 301 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]-4- methyl-6-(1H-pyrazol-3- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 385 (400 MHz, DMSO-d6) dppm 1.20-1.35 (m, 2H) 1.54- 1.61 (m, 2H) 2.09-2.16 (m, 2H) 2.57 (s, 3H)2.71-2.93 (m, 2H) 3.46-3.53 (m, 5H) 4.57 (t, 1H) 5.33-5.56 (m, 1H) 6.94(s, 1H) 7.19 (s, 2H) 7.49-7.66 (m, 1H) 8.35 (s, 1H) 12.95-13.12 (m, 1H)302 I

2-amino-8-[trans-4-(2- hydroxyethoxy) cyclohexyl]-4- methyl-6-(1-methyl-1H-pyrazol-4- yl)pyrido[2,3- d]pyrimidin-7(8H)-one 399 (400 MHz,DMSO-d₆) δ ppm 1.18-1.34 (m, 2H) 1.47- 1.59 (m, 2H) 2.06-2.16 (m, 2H)2.56 (s, 3H) 2.69-2.92 (m, 2H) 3.44-3.53 (m, 5H) 3.86 (s, 3H) 4.58 (t, J= 5.18 Hz, 1H) 5.34-5.57 (m, 1H) 7.05 (br. s., 2H) 8.07 (s, 1H) 8.09 (s,1H) 8.33 (s, 1H) 303 I

2-({cis-4-[2-amino-6- (6-methoxypyridin-3- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 439 (400MHz, DMSO-d6) δ ppm 1.29-1.37 (m, 2H) 1.38- 1.51 (m, 2H) 1.99-2.11 (m,2H) 2.55 (s, 3H) 2.83-3.08 (m, 2H) 3.58-3.67 (m, 1H) 3.82 (s, 2H) 3.88(s, 3H) 5.41-5.66 (m, 1H) 6.84 (d, J = 8.84 Hz, 1H) 7.06-7.24 (m, 3H)7.38 (br. s., 1H) 7.98 (s, 1H) 8.00 (dd, J = 8.59, 2.53 Hz, 1H) 8.42 (d,J = 2.53 Hz, 1H) 304 I

2-({cis-4-[2-amino-6- (5-fluoro-6- methoxypyridin-3-yl)- 4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 457 (400MHz, DMSO-d6) δ ppm 1.24-1.39 (m, 2H) 1.39- 1.53 (m, 2H) 1.95-2.15 (m,2H) 2.57 (s, 3H) 2.81-3.12 (m, 2H) 3.56-3.69 (m, 1H) 3.82 (s, 2H) 3.98(s, 3H) 5.36-5.67 (m, 1H) 7.02- 7.29 (m, 3H) 7.38 (br. s., 1H) 8.00 (dd,J = 12.13, 1.77 Hz, 1H) 8.06 (s, 1H) 8.30 (d, J = 2.02 Hz, 1H) 305 I

2-({cis-4-[2-amino-4- methyl-7-oxo-6-(1H- pyrazol-4- yl)pyrido[2,3-d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 398 (400 MHz, DMSO-d6) δppm 1.26-1.37 (m, 2H) 1.39- 1.52 (m, 2H) 2.00-2.11 (m, 2H) 2.58 (s, 3H)2.89-3.09 (m, 2H) 3.62-3.69 (m, 1H) 3.85 (s, 2H) 5.46-5.68 (m, 1H) 7.01(br. s., 2H) 7.31 (br. s., 1H) 7.49 (br. s., 1H) 8.12 (s, 1H) 8.16 (br.s., 1H) 8.34 (br. s., 1H) 12.85 (br. s., 1H) 306 I

2-({cis-4-[2-amino-4- methyl-6-(1-methyl- 1H-pyrazol-4-yl)-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 412 (400MHz, DMSO-d6) δ ppm 1.27-1.35 (m, 2H) 1.40- 1.50 (m, 2H) 1.99-2.10 (m,2H) 2.57 (s, 3H) 2.86-3.07 (m, 2H) 3.63-3.70 (m, 1H) 3.85 (s, 2H) 3.87(s, 3H) 5.45-5.73 (m, 1H) 7.03 (br. s., 2H) 7.37 (s, 1H) 7.55 (s, 1H)8.10 (d, J = 12.13 Hz, 2H) 8.31 (s, 1H) 307 I

2-({cis-4-[2-amino-6- (2-methoxypyrimidin- 5-yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 440 (400MHz, DMSO-d6) δ ppm 1.28-1.38 (m, 2H) 1.38- 1.51 (m, 2H) 1.98-2.12 (m,2H) 2.56 (s, 3H) 2.84-3.06 (m, 2H) 3.57-3.67 (m, 1H) 3.82 (s, 2H) 3.96(s, 3H) 5.41-5.63 (m, 1H) 7.00- 7.29 (m, 3H) 7.39 (br. s., 1H) 8.13 (s,1H) 8.88 (s, 2H) 308 I

2-{[cis-4-(2-amino-4- methyl-7-oxo-6- quinolin-3- ylpyrido[2,3-d]pyrimidin-8(7H)- yl)cyclohexyl]oxy} acetamide 459 (400 MHz, DMSO-d6) δppm 1.33-1.41 (m, 2H) 1.41- 1.53 (m, 2H) 2.07 (dd, J = 12.51, 0.88 Hz,2H) 2.60 (s, 3H) 2.90-3.11 (m, 2H) 3.61-3.69 (m, 1H) 3.83 (s, 2H)5.48-5.69 (m, 1H) 7.10- 7.32 (m, 3H) 7.39 (br. s., 1H) 7.63 (t, J = 7.33Hz, 1H) 7.76 (ddd, J = 8.40, 7.01, 1.26 Hz, 1H) 8.04 (t, J = 6.95 Hz,2H) 8.23 (s, 1H) 8.64 (d, J = 2.02 Hz, 1H) 9.16 (d, J = 2.02 Hz, 1H) 309I

2-({trans-4-[2-amino- 6-(6-methoxypyridin-3- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 439(400MHz, DMSO-d6) d ppm 1.25-1.39 (m, 2H) 1.50- 1.62 (m, 2H) 2.10-2.20(m, 2H) 2.39-2.45 (m, 2H) 2.55 (s, 3H) 3.38-3.50 (m, 1H) 3.84 (s, 2H)3.88 (s, 3H) 5.30-5.53 (m, 1H) 6.84 (d, J = 8.59 Hz, 1H) 7.08 (br. s.,1H) 7.16 (br. s., 2H) 7.26 (br. s., 1H) 7.98(s, 1H) 7.98- 8.02 (m, 1H)8.41-8.45 (m, 1H) 310 I

2-{[trans-4-(2-amino- 4-methyl-7-oxo-6- quinolin-3- ylpyrido[2,3-d]pyrimidin-8(7H)- yl)cyclohexyl]oxy} acetamide 459 (400 MHz, DMSO-d₆) δppm 1.27-1.41 (m, 2H) 1.58- 1.68 (m, 2H) 2.10-2.23 (m, 2H) 2.29-2.38 (m,2H) 2.61 (s, 3H) 3.58-3.69 (m, 1H) 3.86 (s, 2H) 5.37-5.60 (m, 1H) 7.10(br. s., 1H) 7.26 (br. s., 3H) 7.64 (t, J = 7.45 Hz, 1H) 7.77 (t, J =8.08 Hz, 1H) 8.04 (t, J = 7.45 Hz, 2H) 8.24 (s, 1H) 8.65 (s, 1H) 9.17(s, 1H) 311 I

2-({trans-4-[2-amino- 6-(2- methoxypyrimidin-5- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 440.2(400 MHz, DMSO-d₆) δ ppm 1.34-1.46 (m, 2H) 1.61- 1.72 (m, 2H) 2.16-2.28(m, 2H) 2.64 (s, 3H) 2.80-3.02 (m, 2H) 3.45-3.60 (m, 1H) 3.93 (s, 2H)4.04 (s, 3H) 5.39-5.61 (m, 1H) 7.17 (br. s., 1H) 7.28-7.39 (m, 3H) 8.21(s, 1H) 8.97 (s, 2H) 312 I

2-({trans-4-[2-amino- 4-methyl-7-oxo-6-(1H- pyrazol-4- yl)pyrido[2,3-d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 398.2 (400 MHz, DMSO-d₆)δ ppm 1.27-1.40 (m, 2H) 1.50- 1.61 (m, 2H) 2.08-2.20 (m, 2H) 2.57 (s,3H) 2.72-2.88 (m, 2H) 3.39-3.54 (m, 1H) 3.86 (s, 2H) 5.48 (br. s., 2H)7.05 (br. s., 2H) 7.41 (br. s., 2H) 8.12 (s, 2H) 8.34 (br. s., 1H) 313 I

2-({trans-4-[2-amino- 4-methyl-6-(1-methyl- 1H-pyrazol-4-yl)-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclohexyl}oxy) acetamide 412.2(400 MHz, DMSO-d₆) δ ppm 1.26-1.39 (m, 2H) 1.47- 1.61 (m, 2H) 2.09-2.19(m, 2H) 2.56 (s, 3H) 2.71-2.91 (m, 2H) 3.37-3.55 (m, 1H) 3.85 (s, 5H)5.17-5.88 (m, 1H) 7.01-7.14 (m, 3H) 7.27 (br. s., 1H) 8.08 (d, J = 8.84Hz, 2H) 8.33 (s, 1H) 314 I

2-amino-8-[trans-3-(2- hydroxyethoxy) cyclobutyl]-6-(6-methoxypyridin-3-yl)- 4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 398.2(300 MHz, DMSO-d6) δppm 2.18-2.33 (m, J = 10.46, 10.46 Hz, 2H) 2.56 (s,3H) 3.12- 3.25 (m, 2H) 3.36 (q, J = 5.34 Hz, 2H) 3.54 (q, J = 5.34 Hz,2H) 3.89 (s, 3H) 4.35-4.45 (m, 1H) 4.63 (t, J = 5.37 Hz, 1H) 6.15-6.31(m, J = 8.67, 8.67 Hz, 1H) 6.86 (d, J = 8.67 Hz, 1H), 7.22 (s, 2H),7.96- 8.07 (m, 2H), 8.44 (d, J = 2.45 Hz, 1H) 315 I

2-amino-6-(5-fluoro-6- methoxypyridin-3-yl)- 8-[trans-3-(2-hydroxyethoxy) cyclobutyl]-4- methylpyrido[2,3- d]pyrimidin-7(8H)-one416.2 (300 MHz, DMSO-d6) δppm 2.27 (t, J = 10.46 Hz, 2H) 2.56 (s, 3H)3.10-3.26 (m, 2H) 3.36 (q, J = 5.18 Hz, 2H) 3.54 (q, J = 5.40 Hz, 2H)3.98 (s, 3H) 4.33-4.44 (m, 1H) 4.63 (t, J = 5.46 Hz, 1H) 6.13-6.31 (m,1H, J = 8.85 Hz, 1H) 7.27 (s, 2H) 8.02 (dd, J = 12.15, 1.98 Hz, 1H) 8.08(s, 1H) 8.31 (d, J = 1.88 Hz, 1H) 316 I

2-amino-8-[trans-3-(2- hydroxyethoxy) cyclobutyl]-6-(2-methoxypyrimidin-5- yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 399.2(300 MHz, DMSO-d6) δppm 2.18-2.32 (m, 2H) 2.55 (s, 3H) 3.12-3.24 (m, 2H)3.33- 3.36 (m, 2H) 3.47-3.58 (m, 2H) 3.95 (s, 3H) 4.33-4.47 (m, 1H)4.58-4.70 (m, 1H) 6.15-6.31 (m, 1H) 7.28 (s, 2H), 8.14 (s, 1H), 8.89 (s,2H) 317 I

2-({trans-3-[2-amino- 6-(6-methoxypyridin-3- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclobutyl}oxy) acetamide 411.2(300 MHz, DMSO-d6) δppm 2.28-2.39 (m, 2H) 2.55 (s, 3H) 3.08-3.25 (m, 2H)3.75 (s, 2H) 3.89 (s, 3H) 4.41-4.57 (m, 1H) 6.17-6.31 (m, 1H) 6.86 (d, J= 8.67 Hz, 1H) 7.13 7.37 (m, 4H), 7.95-8.08 (m, 2H), 8.44 (d, J = 2.45Hz, 1H) 318 I

2-({trans-3-[2-amino- 6-(5-fluoro-6- methoxypyridin-3-yl)- 4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclobutyl}oxy) acetamide 429.2(300 MHz, DMSO-d6) δppm 2.32-2.39 (m, 2H) 2.56 (s, 3H) 3.10-3.24 (m, 2H)3.75 (s, 2H) 3.98 (s, 3H) 4.39-4.56 (m, 1H) 6.18-6.30 (m, 1H) 7.08-7.35(m, 4H), 8.02 (dd, J = 12.24, 1.88 Hz, 1H) 8.08 (s, 1H), 8.31 (d, J =1.88 Hz, 1H) 319 I

2-({trans-3-[2-amino- 6-(2- methoxypyrimidin-5- yl)-4-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)- yl]cyclobutyl}oxy) acetamide 412.2(300 MHz, DMSO-d6) δppm 2.24-2.41 (m, 2H) 2.57 (s, 3H) 3.09-3.25 (m, 2H)3.76 (s, 2H) 3.96 (s, 3H) 4.42-4.54 (m, 1H) 6.13-6.35 (m, 1H) 7.19-7.38(m, 4H), 8.16 (s, 1H), 8.90 (s, 2H)

Example 101 PI3-Kα Biochemical Assay

Compounds of the present invention were evaluated for potency againstPI3-Kα using an in vitro kinase assay. PI3-Kα activity is measured invitro by determining the level of phosphorylation of the substratePI(4,5)P₂. The formation of product PI(3,4,5)P₃ is monitored by bindingto the Grip1 PH domain in a ligand displacement fluorescencepolarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P₃complexed with Grip1 PH domain is displaced by PI(3,4,5)P₃ formed in thePI3-Kα reaction resulting in a decrease in FP signal. Mouse PI3-Kα P110and P85 subunits were co-expressed in insect cells and co-purified tohomogeneity. PI(4,5)P₂ were obtained from Cayman. TAMRA-labeledPI(3,4,5)P₃ were from Echelon, Grip1 PH domain from Dundee and otherreagents were from Sigma.

All assays were performed in a Corning solid black 96-well half areaplate using LJL Analyst (Molecular Devices) at room temperature. Theassay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM DTT, and0.05% CHAPS. Dry powder PI(4,5)P₂ was dissolved in 50 mM TRIS, pH 8 tomake 1 mM stock solution. The PI(4,5)P₂ stock solution was then dilutedin the assay buffer to 60 μM, and sonicated for 30 sec before use. Tothe assay plate, the following reagents were added in sequence: 10 μL of60 μM PI(4,5)P₂, 5 μL of 4 nM PI3-Kα, 2 μL of compound in 25% DMSO, 3 μLof mixture containing 200 μM ATP and 33 mM MgCl₂. The final volume forthe reaction was 20 μL. The reaction mixture was incubated at roomtemperature for 35 min. The reaction was then stopped by 20 μL of 20 mMEDTA. After the reaction was stopped, 15 μL of the assay mixture wastransferred to a 96-well half area plate containing 15 μL detectionmixture of 480 nM Grip1 PH domain and 12 nM TAMRA-labeled PI(3,4,5)P₃.The FP signal was allowed to develop for 40 min before reading on a LJLanalyst at excitation 535 nm and emission 580 nm.

The percentage of inhibition was calculated based on the followingequation% inhibition=[1−(FP_(compound)−FP_(max))/(FP_(min)−FP_(max))]×100,where FP_(compound) is the FP reading at a given compound concentration,FP_(min) is the FP signal of the PI3-Kα reaction in the absence of acompound, and FP_(max) is the background FP signal in the absence ofPI3-Kα and a compound. The IC₅₀ was determined by fitting the FP signalvs. compound concentration to a sigmoidal dose response equation usingGraphPad Prism curve fitting program.

Example 102 PI3-Kα Cellular Assay

Compounds of the present invention were evaluated for potency againstPI3-K using a cellular assay as follows. The activity of PI3-K in cellsis determined by measuring the level of phosphorylation of AKT at serine473. AKT Ser phosphorylation is measured using anti-phospho-AKT (Ser473)antibodies (Cell Signaling #4058) in an ELISA format.

Healthy growing human breast cancer cells BT20 (PI3K mutated) are usedfor the assay. BT20 cells are grown in 10% FBS+GLN (1:100)+PS (1:100)+1mM Sodium Pyruvate+0.1 mM Sodium Bicarbonate+Non-Essential Amino AcidsSolution (1:100) MEM medium (MEM+all). When the cells are near85%+confluence, the cells are rinsed with PBS once and are trypsinizedwith trypsin EDTA for 3 minutes. The cells are re-suspended in 10% FBSMEM all and are centrifuged down at 1400 rpm for 5 minutes. The cellsare re-suspended in 0.5% FBS MEM all and are counted on a cell counter.The cells are seeded at 25,000 cells/well in volume of 100 μL/well in0.5% FBS MEM all in a 96 well flat-bottom plate. The negative controlwells receive only 100 μL of 0.5% FBS MEM all medium without cells. Theplate is incubated overnight in a cell culture incubator with 5% CO₂ at37° C.

On day 2, testing compounds are prepared in 0.5% FBS MEM all medium andserially diluted at 1:3 for 11 test concentrations. Each concentrationof the compounds is tested in duplicate. The compound solutions areadded at 25 μL/well to the corresponded wells in cell plate, and 25μL/well of the vehicle (0.5% DMSO in 0.5% FBS MEM all) is added to thenegative control wells (no cells) and the positive control wells (cellswithout compounds). The plate is incubated for 1 hour in a cell cultureincubator with 5% CO₂ at 37° C. After 1 hour of incubation, the mediumis removed, 100 μL/well of cell lysis buffer is added into the cellplate, and shake for 15 minutes at room temperature. After 15 minutes,the cell lysates are transferred to ELISA plate [pre-coated withanti-phospho-AKT (Ser473) rabbit monoclonal antibody, Cell signaling,catalog #4058], and the plate is incubated with gentle shaking for 2hours at room temperature. After 2 hours, empty the contents of thewells, wash plate 4 times with the wash buffer, and add 100 μL ofanti-AKT1 mouse monoclonal detection antibody (Cell signaling, catalog#2967) into each well, incubate with gentle shaking for 1 hour at roomtemperature. After 1 hour, empty the contents of the wells and wash theplate 4 times with the wash buffer, and add 100 μL of anti-mouse IgGHRP-linked antibody (Cell Signaling, catalog #7076) into each well, andincubate the plate with gentle shaking for 1 hour at room temperature.After 1 hour, empty the contents of the wells, wash the plate 4 timeswith the wash buffer, and add 100 μL of TMB substrate solution (catalog#T0440, Sigma) into each well, and incubate with gentle shaking at roomtemperature for 20 minutes. After 15 minutes of color development, add100 μL of stop solution (1N hydrochloric acid) to each well, and readthe plate at 450 nm on ELISA plate reader.

TABLE 2 PI3-Kα Biochemical and Cellular Activity Data PI3-Kα PI3-KαPI3-Kα Cellular Biochemical Biochemical COMPOUND Assay Assay AssayNUMBER IC₅₀ μM IC₅₀ μM % Inhibition 101 0.00349 0.011 102 0.0179 0.015103 2.33 0.4 104 10 43 at 10 μM 105 0.234 0.024 106 0.495 0.045 1070.305 0.023 108 0.00382 0.00157 99 at 10 μM 109 0.0584 0.0063 99 at 10μM 110 0.106 0.017 111 0.0161 0.00296 112 0.0742 0.0391 113 0.0952 0.021114 1.18 0.11 115 0.00382 0.00075 116 5.75 0.83 117 10 32 at 10 μM 1188.37 1.1 119 5.71 0.31 120 0.896 0.042 121 10 27 at 50 μM 122 10 1230.65 0.068 124 0.00258 0.008 125 9.01 1.43 126 5.48 0.856 127 0.002760.00048 128 3.53 0.275 129 2.75 0.004 130 10 0.054 131 7.98 3.4 132 105.5 133 0.603 0.06 134 8.3 2.1 135 0.0461 0.00177 136 0.0263 0.00308 1370.019 0.000989 138 0.146 0.0297 139 0.017 0.00503 140 0.000793 0.00103141 10 7.08 142 1.39 0.792 143 0.669 0.244 144 0.00305 0.00101 145 0.6220.168 146 0.00176 0.000731 147 0.00484 0.000524 148 0.0147 0.00478149 >10 0.31 150 >10 1.4 151 >10 4.9 152 0.0036 0.024 153 2.76 0.46 1540.475 0.018 155 0.0829 0.011 156 0.169 0.0067 157 0.305 0.044 158 0.03190.0013 159 0.0876 0.0046 160 1.04 0.15 161 0.934 0.055 162 0.0472 0.014163 0.0204 0.0012 164 1.3 0.036 165 0.0558 0.0012 166 0.262 0.0095 1672.36 0.68 168 0.228 0.13 169 0.34 0.088 170 10 3.4 171 0.0254 0.0016 1720.116 0.015 173 0.322 0.27 174 0.019 0.0076 175 0.0193 0.0043 1760.00466 0.012 177 0.00802 0.0024 178 0.064 0.031 179 0.00737 0.0039 1800.00339 0.0016 181 0.0176 0.012 182 0.0101 0.0062 183 0.00469 0.009 1840.211 0.11 185 0.0152 0.018 186 0.0252 0.01 187 0.0172 0.0095 188 0.07180.0094 189 0.0212 0.0027 190 2.69 0.47 191 0.0031 0.0011 192 0.005080.093 193 0.00701 0.028 194 0.00597 0.0059 195 0.0757 0.023 196 0.03660.0045 197 0.236 0.188 198 0.262 0.13 199 0.0199 0.0185 200 0.07140.0066 201 0.0153 0.0037 202 1.67 0.23 203 0.0258 0.02 204 0.143 0.0075205 0.0167 0.015 206 0.0265 0.0082 207 0.0119 0.002 208 0.00964 0.0294209 0.064 0.011 210 0.00677 0.0023 211 0.399 0.078 212 0.176 0.056 2130.138 0.017 214 0.594 0.048 215 0.0221 0.006 216 0.0456 0.0046 2170.0135 0.0016 218 1.02 0.094 219 0.0949 0.014 220 0.145 0.0077 2210.0578 0.0028 222 2.13 0.1 223 0.249 0.022 224 0.12 0.021 225 0.03660.0054 226 0.0415 0.12 227 0.318 0.029 228 0.256 0.038 229 0.0179 0.015230 0.0339 0.02 231 3.45 0.17 232 0.0414 0.0089 233 0.0942 0.011 2340.314 0.039 235 0.623 0.032 236 10 0.046 237 0.397 0.012 238 4.53 0.34239 1.27 0.3 240 0.101 0.089 241 0.0793 0.01 242 0.0884 0.015 243 0.3160.018 244 0.437 0.03 245 0.181 0.067 246 0.172 0.027 247 0.671 0.2 2480.127 0.007 249 0.121 0.0063 250 0.0164 0.00234 251 0.0283 0.00059 2520.055 0.0029 253 0.00492 0.019 254 0.00792 0.0017 255 0.00957 0.002 2560.0202 0.0031 257 0.0231 0.011 258 0.0265 0.088 259 0.0267 0.045 2600.0332 0.0039 261 0.0348 0.004 262 0.0459 0.015 263 10 3.3 264 0.5560.062 265 0.00143 266 0.0493 0.0022 267 10 0.81 268 2.52 0.3 269 2.090.095 270 0.657 0.11 271 0.042 0.0082 272 0.0437 0.0044 273 0.02510.0023 274 0.00781 0.0018 275 0.0468 0.012 276 0.0051 0.000788 2770.0206 0.00159 278 0.0505 0.00130 279 0.0305 0.0029 280 0.0039 281 >101.2 282 0.265 0.017 283 0.0722 0.005 285 0.018 0.0099 286 0.0131 0.00485287 0.0389 0.0022 288 0.0053 0.00144 289 0.0295 0.0176 290 0.03350.00758 291 0.0965 0.0552 292 0.0121 0.00928 293 0.0153 0.00531 2940.0026 295 0.0962 0.0529 296 0.0091 0.0297 299 0.00735 0.000686 3000.0132 0.00682 301 0.137 0.0146 302 0.226 0.0223 303 0.0205 0.00387 3040.00768 0.00158 305 0.148 0.0148 306 0.998 0.0581 307 0.0829 0.00362 3080.116 0.0177 309 0.0193 0.00579 310 0.0555 0.0113 311 0.0519 0.00411 3120.256 0.0135 313 0.376 0.0479 314 0.0508 0.0102 315 0.0146 0.00311 3160.0935 0.00665 317 0.0335 0.00472 318 0.0126 0.00214 319 0.11 0.00591

Example 103 Mouse Xenograft Efficacy Studies

The in vivo efficacy of2-amino-8-(trans-4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Compound 152) disclosed in Example 53 was examined in s.c. xenograftmodel. Human tumor cell lines PC3 (PTEN deletion)), U87MG (PTENdeletion) and SKOV3 (PI3Kα H1047K) were chosen for in vivo efficacystudies due to their different genetic background and relatively highlevels of phospho AKT S473 signal. Cells were implanted in the hindflank of athymic mice and tumors grew in size to 100-200 mm³ beforedaily oral treatment with Compound 152 was initiated. Compound 152exhibited dose-dependent anti-tumor efficacy in each tumor model,resulting in regression of PC3, growth inhibition of SKOV3 and U87MGtumors. Data are summarized in Table 3 and representative examples areshown in FIGS. 1-3. For all models tested 1 mg/kg was an efficaciousdose.

Animal Care: Female and male athymic mice (6-8 weeks old) weighing ˜22 gwere obtained from Charles River Laboratory. Animal were housed on a 12h light/dark cycle in the Pfizer vivarium and all procedures areconducted in accordance with the Pfizer Institutional Animal Care andUse Committee (IACUC). Animals are provided free access to rodent chowand water ad libitum and maintained under clean room conditions. Priorto study start animals acclimate for at least 48 h.

Cell lines: All cell lines were cultured at 37° C. in humidified 5% CO₂incubator. U87 MG glioblastoma tumor cell line was obtained fromAmerican Type Culture Collection (ATCC) and cultured with DMEMsupplemented with 15% FBS and 2 mM glutamine. PC3 prostate cancer cellline were obtained from National Cancer Institute and cultured in RPMImedia supplemented with 10% FBS and 2 mM glutamine. SKOV3 ovarian cancercells were obtained from ATCC and passaged multiple times through mice,and cultured in McCoy's 5A media supplemented with 10% FBS and 2 mMglutamine. All cell lines were tested by University of Missouri ResearchAnimal Diagnostic Laboratory for known species of murine viruses andmycoplasma contamination.

Mouse Xenograft Models: U87MG (glioblastoma), PC3 (prostate cancer) andSKOV3 (ovarian cancer) cell lines in culture were harvested bytrypsinisation. Briefly, 2.5-4×10⁶ tumor cells were suspended in themedium used to culture each cell line without serum and implantedsub-cutaneously (s.c) into the hind flank region of mice on day 0. Dailytreatment with Compound 152, formulated in 10% ethanol, 40% PEG and 50%sodium citrate buffer or vehicle alone commenced 10-14 d afterimplantation when average tumors were 100-200 mm³ in size.

Tumors were measured twice weekly and tumor volume was calculated as aproduct of (length×width²)/2. Studies were typically terminated when thetumor in the vehicle treated animals reached a size of >1500 mm3 or whenjudged to adversely affect the well being of the animal. At the end ofthe study percentage of tumor growth inhibition values were calculatedas 100×(1−[(tumor volume_(final)−tumor volume_(initial) for thecompound-treated group)/(tumor volume_(final)−tumor volume_(initial) forthe vehicle-treated group)]). Where applicable, percent tumor regressionfor each group was calculated as 100×(tumor volume_(initial)−tumorvolume_(final))/(tumor volume_(initial)). A cohort of 12 animals wasused for each dose group for efficacy studies. A representative cohortof animals were sacrificed at the times indicated, tumors resected, anda blood sample taken from the cardiac left ventricle and immediatelyplaced in a vial primed with heparin sulfate. Typically one half of thetumor was fixed in 10% neutral buffered formalin, paraffin embedded, andsectioned for immunohistochemistry. The other half was frozen in liquidnitrogen and later processed to generate cell lysates for targetmodulation studies.

TABLE 3 Mouse Xenograft Efficacy Data Initial tumor Tumor volume DoseGrowth Regressionn Cell line Type (mm3) mg/kg/day Inhibition (%) (%) PC3Prostate 126 0.25 45 126 0.5 62 124 1 89 125 2 19 SKOV3 Ovarian 146 0.546 146 1 66 146 2 82 U87 MG Glioma 134 0.1 18 135 0.3 56 135 1.0 76

Example 104 In Vivo Target Modulation Studies

In vivo target modulation studies to determine the effect of Compound152 treatment on the phosphorylation of AKT on S473 by ELISA and S6 onS235/S236 by IHC were performed. Resected tumors were frozen on dry iceand pulverized using the FAST PREP instrument (Qbiogene). Briefly,frozen tumors were placed in Fast Prep matrix tubes, cold lysis buffer[20 mM HEPES (pH 7.5), 150 mM NaCl, 1.0 mM sodium EDTA, 1% Triton X-100,2.5 mM sodium pyrophosphate, 1 mM sodium orthovanadate, 1 μg/mlleupeptin, and 1 mM PMSF] was added and samples were centrifuged for 5sec, mixed and process repeated two more times. Samples were centrifugedin a cold refrigerated Eppendorf centrifuge at 14,000 RPM for 20 min.Supernatant was collected and total and phosphoAKT (S473) protein levelsdetermined by ELISA. The extent of phosphorylation in tumors resectedfrom treated animals was compared with that in tumors resected fromvehicle-treated animals at the same time point. Plasma samples, obtainedby centrifuging individual blood samples at 3000×g for 5 min at 4° C. inan Eppendorf 5417R centrifuge, were stored at −80° C. until they couldbe analyzed for drug concentration. Briefly, plasma samples (50 μl) orCompound 152 standards in mouse plasma were mixed with acetonitrile 3μl) and injected onto a LC/MS/MS system where separation occurred on aC-18 SB phenyl (5 μM, 2.1×50 mm, Agilent) reverse-phase high-performanceliquid chromatography column. The amount of inhibitor and the internalstandard (0.5 μM buspirone) in each mouse plasma sample was quantifiedbased on standard curves generated using known amounts of compound.Compound 152 treatment resulted in dose dependent inhibition of pAKT atS473 in all 3 models discussed above. Time course and dose response ofin vivo target modulation and plasma inhibitor concentrations weredetermined post last dose at the end of the efficacy study describedabove and data are summarized in Table 4. For the U87MG model the EC₅₀Compound 152 plasma concentration for pAKT S473 target modulation wascalculated as 24 nM and correlated to 50% tumor growth inhibition.

TABLE 4 Pharmacokinetic and Pharmacodynamic (PK-PD) correlation inxenograft models p-Akt/Akt (%) Free plasma conc (nM) Cell Line 1 h 3 h 7h 24 h 1 h 3 h 7 h 24 h PC3 0.25 mg/kg  42 ± 14  82 ± 18 137 ± 23 29 140  0.5 mg/kg 32 ± 4 38 ± 5 107 ± 6  59 37 0   1 mg/kg  23 ± 10 27 ± 9113 ± 15 118 86 0   2 mg/kg 21 ± 5 17 ± 7 78 ± 9 189 185 8 SKOV3  0.5mg/kg 30 ± 3 55 ± 4 147 ± 21 74 49 0   1 mg/kg 27 ± 6  48 ± 17 124 ± 10158 95 0   2 mg/kg 23 ± 5  30 ± 13 126 ± 20 298 214 8 U87  0.1 mg/kg 4426  0.3 mg/kg 27 85   1 mg/kg 11 238

1. A compound of Formula (I)

or a salt thereof, wherein: R¹ is H or (C₁ to C₆) alkyl optionallysubstituted with at least one R⁵ group; A is a 3 to 10 memberedcycloalkyl group; R² is (C₁ to C₆) alkyl substituted with at least oneR⁶ group, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ toC₁₄) aryl, (C₂ to C₉) heteroaryl, —NR^(7a)R^(7b), or —N═CR^(8a)R^(8b)wherein each of the said (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, (C₆ to C₁₄) aryl, and (C₂ to C₉) heteroaryl isoptionally substituted with at least one R⁹ group; R³ is (C₁ to C₆)alkyl, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₈)alkenyl, (C₂ to C₈) alkynyl, halogen, cyano, —(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), COR¹², (C₆ to C₁₄) aryl, or (C₂ to C₉)heteroaryl, wherein said (C₁ to C₆) alkyl, (C₃ to C₁₀) cycloalkyl, (C₂to C₉) cycloheteroalkyl, (C₂ to C₈) alkenyl, (C₂ to C₈) alkynyl, (C₆ toC₁₄) aryl and (C₂ to C₉) heteroaryl is optionally substituted with atleast one R⁹ group; each R⁴ is independently —OH, halogen, CF₃,—NR^(11a)R^(11b), (C₁ to C₆) alkyl, (C₂ to C₆) to alkenyl, (C₂ to C₆)alkynyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉) heteroaryl, —C(O)R¹²,—C(O)NR^(11a)R^(11b), —S(O)_(m)R¹², —S(O)_(m)NR^(11a)R^(11b),—NR^(11a)S(O)_(m)R¹², —(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₁ to C₆)alkyl, (C₂ to C₆) alkenyl, (C₂ to C₆) alkynyl, (C₁ to C₆) alkoxy, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, and (C₂to C₉) heteroaryl is optionally substituted with at least one R¹³ group;each R⁵ is independently —OH, halogen, CF₃, —NR^(11a)R^(11b), (C₁ to C₆)alkyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉)cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉) heteroaryl, —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —C(O)R¹² or —C(O)NR^(11a)R^(11b) wherein eachof the said (C₁ to C₆) alkyl, (C₁ to C₆) alkoxy, (C₃ to C₁₀) cycloalkyl,(C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, and (C₂ to C₉) heteroarylis optionally substituted with at least one R⁹ group; each R⁶ isindependently —OH, (C₂ to C₆) alkynyl, cyano, (C₃ to C₁₀) cycloalkyl,(C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉) heteroaryl,—C(O)R¹², —C(O)NR^(11a)R^(11b), —S(O)_(m)R¹², —S(O)_(m)NR^(11a)R^(11b),—NR^(11a)S(O)_(m)R¹², —(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₂ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ toC₁₄) aryl, and (C₂ to C₉) heteroaryl is optionally substituted with atleast one R¹³ group; R^(7a) and R^(7b) are each independently H, (C₁ toC₆) alkyl, (C₂ to C₆)alkenyl, (C₂ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl,or (C₆ to C₁₀)aryl, wherein each of the said (C₁ to C₆) alkyl, (C₂ toC₆)alkenyl, (C₂ to C₆)alkynyl, (C₃ to C₁₀) cycloalkyl, and (C₆ toC₁₀)aryl is optionally substituted with at least one R⁹ group; or R^(7a)and R^(7b) may be taken together with the nitrogen atom to form a 5 to 8membered cycloheteroalkyl ring, wherein said heterocyclyl ring has 1 to3 ring heteroatoms selected from the group consisting of N, O, and S andwherein the said 5 to 8 membered cycloheteroalkyl ring is optionallysubstituted with at least one R⁹ group; R^(8a) and R^(8b) are eachindependently H, (C₁ to C₆) alkyl, or (C₃ to C₁₀) cycloalkyl whereineach of the said (C₁ to C₆) alkyl, and (C₃ to C₁₀) cycloalkyl, isoptionally substituted with at least one R⁹ group; each R⁹ isindependently —OH, halogen, CF₃, —NR^(11a)R^(11b), (C₁ to C₆) alkyl, (C₂to C₆) alkenyl, (C₂ to C₆) alkynyl, (C₁ to C₆) alkoxy, cyano, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ toC₉) heteroaryl, —C(O)R¹², —C(O)NR^(11a)R^(11b), —S(O)_(m)R¹²,—S(O)_(m)NR^(11a)R^(11b), —NR^(11a)S(O)_(m)R¹², —(CH₂)_(n)C(O)OR¹⁰,—(CH₂)_(n)C(O)N(R^(11a)R^(11b)), —OC(O)R¹², —NR^(11a)C(O)R¹² or—NR^(11a)C(O)N(R^(11a)R^(11b)) wherein each of the said (C₁ to C₆)alkyl, (C₂ to C₆) alkenyl, (C₂ to C₆) alkynyl, (C₁ to C₆) alkoxy, (C₃ toC₁₀) cycloalkyl, (C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, and (C₂to C₉) heteroaryl is optionally substituted with at least one R¹³ group;each R¹⁰ is independently H, or (C₁ to C₆) alkyl; R^(11a) and R^(11b)are each independently H, (C₁ to C₆) alkyl, (C₂ to C₉) cycloheteroalkyl,(C₂ to C₉) heteroaryl, or (C₆ to C₁₂) aryl wherein each of the said (C₁to C₆) alkyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, and(C₆ to C₁₂) aryl is optionally substituted with at least one R¹³ group;each R¹² is independently (C₁ to C₆) alkyl, (C₃ to C₁₀) cycloalkyl, (C₂to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, or (C₆ to C₁₄) arylwherein each of the said (C₁ to C₆) alkyl, (C₃ to C₁₀) cycloalkyl, (C₂to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, and (C₆ to C₁₄) aryl isoptionally substituted with at least one R¹³ group; each R¹³ isindependently —OH, halogen, CF₃, (C₁ to C₆) alkyl, (C₂ to C₆) alkenyl,(C₂ to C₆) alkynyl, (C₁ to C₆) alkoxy, cyano, (C₃ to C₁₀) cycloalkyl,(C₂ to C₉) cycloheteroalkyl, (C₆ to C₁₄) aryl, (C₂ to C₉) heteroaryl,amino, C-amido, S-sulfonamido, C-carboxyl, N-amido, or N-carbamyl; eachm is independently 1 or 2; each n is independently 0, 1, 2, 3, or 4; andeach z is independently 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 2. The compound orsalt according to claim 1, wherein A is cyclohexyl.
 3. The compound orsalt according to claim 1, wherein R³ is (C₆ to C₁₄) aryl or (C₂ to C₉)heteroaryl, wherein said (C₆ to C₁₄) aryl or (C₂ to C₉) heteroaryl isoptionally substituted with at least one R⁹ group.
 4. A pharmaceuticalcomposition, comprising at least one compound or salt according to claim1 and a pharmaceutically acceptable carrier or diluent.
 5. The compoundor salt according to claim 1, wherein A is selected from the groupconsisting of cyclobutyl, cyclopentyl, and cyclohexyl.
 6. The compoundor salt according to 1, wherein A is selected from the group consistingof cyclobutyl, cyclopentyl, and cyclohexyl; and R³ is (C₆ to C₁₄) arylor (C₂ to C₉) heteroaryl, wherein said (C₆ to C₁₄) aryl or (C₂ to C₉)heteroaryl is optionally substituted with at least one R⁹ group.
 7. Thecompound or salt according to claim 6, wherein R³ is (C₂ to C₉)heteroaryl, wherein said (C₂ to C₉) heteroaryl is optionally substitutedwith at least one R⁹ group.
 8. The compound or salt according to claim7, wherein A is cyclohexyl.
 9. The compound or salt according to claim6, wherein and R³ is (C₆ to C₁₄) aryl, wherein said (C₆ to C₁₄) aryl isoptionally substituted with at least one R⁹ group.
 10. The compound orsalt according to claim 9, wherein A is cyclohexyl.
 11. The compound orsalt according to claim 1, wherein: R¹ is H; A is selected from thegroup consisting of cyclobutyl, cyclopentyl, and cyclohexyl; R³ is (C₆to C₁₄) aryl or (C₂ to C₉) heteroaryl, wherein said (C₆ to C₁₄) aryl or(C₂ to C₉) heteroaryl is optionally substituted with at least one R⁹group; and z is
 0. 12. The compound or salt according to claim 11,wherein R³ is (C₆ to C₁₄) aryl, wherein said (C₆ to C₁₄) aryl isoptionally substituted with at least one R⁹ group.
 13. The compound orsalt according to claim 12, wherein A is cyclohexyl.
 14. The compound orsalt according to claim 11, wherein R³ is (C₂ to C₉) heteroaryl, whereinsaid (C₂ to C₉) heteroaryl is optionally substituted with at least oneR⁹ group.
 15. The compound or salt according to claim 14, wherein A iscyclohexyl.